Publications by authors named "Hiromichi Ebi"

57 Publications

CIRCULATE-Japan: Circulating tumor DNA-guided adaptive platform trials to refine adjuvant therapy for colorectal cancer.

Cancer Sci 2021 May 1. Epub 2021 May 1.

Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.

Adjuvant chemotherapy has reduced the risk of tumor recurrence and improved survival in patients with resected colorectal cancer. Potential utility of circulating tumor DNA at pre- and post-surgery has been reported across various solid tumors. We initiated a new type of adaptive platform trials to evaluate the clinical benefits of circulating tumor DNA analysis and refine precision adjuvant therapy for resectable colorectal cancer, named CIRCULATE-Japan including three clinical trials. The GALAXY study is a prospectively-conducted large-scale registry designed to monitor circulating tumor DNA for patients with clinical stage II to IV or recurrent colorectal cancer who can undergo complete surgical resection. The VEGA trial is a randomized phase III study designed to test if postoperative surgery alone is non-inferior to the standard therapy with capecitabine plus oxaliplatin for 3 months in patients with high-risk stage II or low-risk stage III colon cancer if circulating tumor DNA status is negative at week 4 after curative surgery in the GALAXY study. The ALTAIR trial is a, double-blind, phase III study designed to establish the superiority of trifluridine/tipiracil as compared with placebo in patients with resected colorectal cancer who show circulating tumor-positive status in GALAXY study. Therefore, CIRCULATE-Japan encompasses both "de-escalation" and "escalation" trials for circulating tumor DNA-negative and positive patients, respectively, and helps to answer whether measuring circulating tumor DNA postoperatively has prognostic and/or predictive value. Our circulating tumor DNA -guided adaptive platform trials will accelerate clinical development toward further precision oncology in the field of adjuvant therapy.
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http://dx.doi.org/10.1111/cas.14926DOI Listing
May 2021

BIG BANG study (EPOC1703): multicentre, proof-of-concept, phase II study evaluating the efficacy and safety of combination therapy with binimetinib, encorafenib and cetuximab in patients with BRAF non-V600E mutated metastatic colorectal cancer.

ESMO Open 2020 30;5(1):e000624. Epub 2020 Sep 30.

Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.

Background: While the BRAF V600E mutation occurs in 5%-15% of metastatic colorectal cancer (mCRC), BRAF non-V600E mutations were recently reported to range from 1.6% to 5.1%. We have previously reported that BRAF non-V600E mutations could have a negative impact on efficacy outcomes as well as BRAF V600E mutation for antiepidermal growth factor receptor (EGFR) antibody treatment for pretreated patients with mCRC. Recently, simultaneous inhibitions of mitogen-activated protein kinase kinase (MEK), BRAF and EGFR exhibited relevant antitumour activities in patients with BRAF V600E mutant and also in BRAF non-V600E mutant but only in the preclinical model.

Trial Design: The BIG BANG (study is a multicentre, phase II study to assess the efficacy, safety and proof of concept of the combinations of binimetinib+encorafenib+cetuximab in patients with BRAF non-V600E mutated mCRC, identified by either tumour tissue (tumour tissue group) or blood samples (liquid biopsy group). Key eligibility criteria include Eastern Cooperative Oncology Group Performance Status of ≤1, mCRC with BRAF non-V600E mutant and RAS wild type, refractory or intolerant to at least one fluoropyrimidine-based regimen and no prior history of regorafenib, and no prior history of anti-EGFR antibody treatment (primary analysis cohort and liquid biopsy cohort) or refractory to prior anti-EGFR antibody treatment in patients with class 3 BRAF mutations (anti-EGFR antibody refractory class three cohort). Enrolled patients receive binimetinib (45 mg, two times per day), encorafenib (300 mg, once a day) and cetuximab (initially 400 mg/m and subsequently 250 mg/m, once per week). The primary endpoint is the confirmed objective response rate in the primary analysis cohort.

Trial Registration Numbers: UMIN000031857 and 000031860.
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http://dx.doi.org/10.1136/esmoopen-2019-000624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7046405PMC
September 2020

FMS-like tyrosine kinase 3 (FLT3) amplification in patients with metastatic colorectal cancer.

Cancer Sci 2021 Jan 20;112(1):314-322. Epub 2020 Nov 20.

Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.

FMS-like tyrosine kinase 3 (FLT3) plays a key role in hematopoiesis. However, the oncogenic role of FLT3 amplification in patients with metastatic colorectal cancer (mCRC) remains unclear. Here, we aimed to evaluate the characteristics, prognosis, and treatment efficacy of an FLT3 inhibitor (regorafenib) in patients with mCRC with FLT3 amplifications. Tumor tissue samples from 2329 patients were sequenced using NGS in the Nationwide Cancer Genome Screening Project in Japan. The effects of clinicopathological features, co-altered genes, prognosis, and efficacy of regorafenib were investigated. Between April 2015 and June 2018, 85 patients with mCRC with FLT3 amplification were observed. There were no differences in baseline characteristics between patients with or without FLT3 amplification. The frequency of RAS or other gene co-alterations was inversely correlated with the copy number status. Median survival time in patients with FLT3 amplification was significantly shorter compared with those with non-FLT3 amplification. Further investigations of FLT3 amplification as a potential treatment target in mCRC are warranted.
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http://dx.doi.org/10.1111/cas.14693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780005PMC
January 2021

Precision Oncology and the Universal Health Coverage System in Japan.

JCO Precis Oncol 2019 11;3. Epub 2019 Dec 11.

Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan.

Although precision oncology is transforming clinical management of patients with cancer, many hospitals face challenges to effectively implement precision oncology. In addition, the cost and time exerted for genomic profiling needs to be balanced with expectations of benefit for each patient. This article summarizes the effort to implement precision oncology in Japan. The most promising development is that tests to profile the genomes of select cancers are now fully covered by the national health insurance system. In May 2019, two gene panels were approved with reimbursement: FoundationOne CDx Cancer Genomic Profile and OncoGuide NCC Oncopanel System, the latter of which was developed in Japan. To make better use of scarce resources, the reimbursement is restricted to patients with solid tumors that have progressed on standard chemotherapy, rare tumors, or tumors of unknown primary. To centralize Japanese precision oncology, the government designated approximately 170 hospitals and stratified them to three layers on the basis of their roles. In addition, Japan's National Cancer Center launched a Center for Cancer Genomics and Advanced Therapeutics (C-CAT) that collects genomic information and clinical characteristics of patients who received genomic profiling tests. C-CAT is expected to be the central data repository, to match patients with clinical trials, and to assist translational research. The centralized system under the national health insurance system could be a double-edged sword. Although tight regulation may make it hard to keep up with the rapid development of precision oncology, a federated ecosystem for sharing clinical and genomic data will be a precious asset and allow for shared access to data. Access to unapproved drugs and administrative support from C-CAT will be keys for Japanese precision oncology to meet its full potential.
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http://dx.doi.org/10.1200/PO.19.00291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446489PMC
December 2019

Epithelial-to-Mesenchymal Transition is a Cause of Both Intrinsic and Acquired Resistance to KRAS G12C Inhibitor in KRAS G12C-Mutant Non-Small Cell Lung Cancer.

Clin Cancer Res 2020 11 8;26(22):5962-5973. Epub 2020 Sep 8.

Division of Molecular Therapeutics, Aichi Cancer Center Research Institute, Nagoya, Japan.

Purpose: is among the most commonly mutated oncogene in cancer including non-small cell lung cancer (NSCLC). In early clinical trials, inhibitors targeting G12C-mutant KRAS have achieved responses in some patients with NSCLC. Possible intrinsic and acquired resistance mechanisms to KRAS G12C inhibitors are not fully elucidated and will likely become important to identify.

Experimental Design: To identify potential resistance mechanisms, we defined the sensitivity of a panel of KRAS G12C-mutant lung cancer cell lines to a KRAS G12C inhibitor, AMG510. Gene set enrichment analyses were performed to identify pathways related to the sensitivity, which was further confirmed biochemically. In addition, we created two cell lines that acquired resistance to AMG510 and the underlying resistance mechanisms were analyzed.

Results: KRAS expression and activation were associated with sensitivity to KRAS G12C inhibitor. Induction of epithelial-to-mesenchymal transition (EMT) led to both intrinsic and acquired resistance to KRAS G12C inhibition. In these EMT-induced cells, PI3K remained activated in the presence of KRAS G12C inhibitor and was dominantly regulated by the IGFR-IRS1 pathway. We found SHP2 plays a minimal role in the activation of the PI3K pathway in contrast to its critical role in the activation of the MAPK pathway. The combination of KRAS G12C inhibitor, PI3K inhibitor, and SHP2 inhibitor resulted in tumor regressions in mouse models of acquired resistance to AMG510.

Conclusions: Our findings suggest that EMT is a cause of both intrinsic and acquired resistance by activating the PI3K pathway in the presence of KRAS G12C inhibitor.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2077DOI Listing
November 2020

Serum concentration of the CKD4/6 inhibitor abemaciclib, but not of creatinine, strongly predicts hematological adverse events in patients with breast cancer: a preliminary report.

Invest New Drugs 2021 Feb 27;39(1):272-277. Epub 2020 Aug 27.

Department of Breast Oncology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, Aichi, 464-8681, Japan.

Purpose The CKD4/6 inhibitor abemaciclib is related to adverse events such as hematological toxicity and increase in serum creatinine levels associated with abemaciclib pharmacokinetics. Increase in serum creatinine levels is considered a result of competition with abemaciclib via organic cation transporter 2 and multidrug and toxic compound extrusion. Therefore, we evaluated the association among serum creatinine levels, serum abemaciclib concentrations, and adverse events and whether increase in serum creatinine levels is a useful indicator for predicting the onset of the adverse events of abemaciclib. Methods In total, the data of 12 patients with breast cancer who were treated with abemaciclib (150 mg twice daily) were evaluated to determine the association between increased serum creatinine levels and abemaciclib concentrations and hematological toxicity. Results Grade 3 neutropenia, thrombocytopenia, and anemia were observed at 4 weeks in four (33%), two (17%), and one (8%) patients, respectively. A significant association was observed between steady-state abemaciclib concentrations and the rate of decrease in neutrophil and platelet counts (r = - 0.80, P = 0.003 and r = - 0.70, P = 0.016, respectively). Compared with baseline levels (0.61 [0.53-0.82] mg/mL), serum creatinine levels significantly increased and reached a steady state in at least 2 weeks (0.84 [0.61-1.02] mg/mL, P = 0.01). However, we did not find a significant association between increase in serum creatinine levels and abemaciclib concentrations and hematological toxicity. Conclusions Abemaciclib concentrations are associated with neutropenia and thrombocytopenia. However, increase in serum creatinine levels may not be a useful predictor for estimating abemaciclib pharmacokinetics and hematological toxicity.
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http://dx.doi.org/10.1007/s10637-020-00994-3DOI Listing
February 2021

Japanese Society of Medical Oncology Clinical Guidelines: Molecular Testing for Colorectal Cancer Treatment, 4th edition.

Cancer Sci 2020 Oct 4;111(10):3962-3969. Epub 2020 Sep 4.

Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka, Japan.

Molecular testing to select the appropriate targeted and standard of care therapies is essential for managing patients with colorectal cancer (CRC). The Japanese Society of Medical Oncology previously published clinical guidelines for molecular testing in CRC. In the third edition published in 2018, RAS and BRAF V600E mutations should be tested prior to first-line chemotherapy to assess the benefit of anti-epidermal growth factor receptor (EGFR) antibody therapy in patients with unresectable CRC. Microsatellite instability (MSI) testing was recommended in patients with curatively resected stage II CRC because deficient mismatch repair is associated with low risk of recurrence. MSI testing was also recommended in patients with CRC suspected to be Lynch syndrome. The main aim of this fourth edition is to reflect recent advances in comprehensive genomic profiling (CGP) tests and liquid biopsy. Here, CGP tests performed on tumor tissues are strongly recommended to assess the benefit of molecular targeted drugs in patients with CRC. Circulating tumor DNA (ctDNA)-based CGP tests are also proposed. ctDNA testing is recommended to determine the optimal treatment based on the risk of recurrence for curatively resected CRC and evaluate the suitability and monitor the therapeutic effects of anti-EGFR antibodies in patients with unresectable CRC. While both MSI testing and immunohistochemistry are strongly recommended to determine the indication of immune checkpoint inhibitors in patients with unresectable CRC, next-generation sequencing-based tests are weakly recommended because these tests have not been validated in clinical trials.
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http://dx.doi.org/10.1111/cas.14567DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540970PMC
October 2020

Genome-wide association meta-analysis identifies GP2 gene risk variants for pancreatic cancer.

Nat Commun 2020 06 24;11(1):3175. Epub 2020 Jun 24.

Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, Nagoya, 464-8681, Japan.

Pancreatic cancer is the fourth leading cause of cancer-related deaths in Japan. To identify risk loci, we perform a meta-analysis of three genome-wide association studies comprising 2,039 pancreatic cancer patients and 32,592 controls in the Japanese population. Here, we identify 3 (13q12.2, 13q22.1, and 16p12.3) genome-wide significant loci (P < 5.0 × 10), of which 16p12.3 has not been reported in the Western population. The lead single nucleotide polymorphism (SNP) at 16p12.3 is rs78193826 (odds ratio = 1.46, 95% confidence interval = 1.29-1.66, P = 4.28 × 10), an Asian-specific, nonsynonymous glycoprotein 2 (GP2) gene variant. Associations between selected GP2 gene variants and pancreatic cancer are replicated in 10,822 additional cases and controls of East Asian origin. Functional analyses using cell lines provide supporting evidence of the effect of rs78193826 on KRAS activity. These findings suggest that GP2 gene variants are probably associated with pancreatic cancer susceptibility in populations of East Asian ancestry.
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http://dx.doi.org/10.1038/s41467-020-16711-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7314803PMC
June 2020

Respecting your elders: osimertinib demonstrates preferential activity in elderly patients with T790M positive non-small cell lung cancers.

J Thorac Dis 2019 Sep;11(Suppl 15):S1844-S1846

Philips Institute for Oral Health Research, VCU School of Dentistry and Massey Cancer Center, Richmond, VA, USA.

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http://dx.doi.org/10.21037/jtd.2019.08.122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6783766PMC
September 2019

PTEN Loss Mediates Clinical Cross-Resistance to CDK4/6 and PI3Kα Inhibitors in Breast Cancer.

Cancer Discov 2020 01 8;10(1):72-85. Epub 2019 Oct 8.

Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts.

The combination of CDK4/6 inhibitors with antiestrogen therapies significantly improves clinical outcomes in ER-positive advanced breast cancer. To identify mechanisms of acquired resistance, we analyzed serial biopsies and rapid autopsies from patients treated with the combination of the CDK4/6 inhibitor ribociclib with letrozole. This study revealed that some resistant tumors acquired RB loss, whereas other tumors lost PTEN expression at the time of progression. In breast cancer cells, ablation of , through increased AKT activation, was sufficient to promote resistance to CDK4/6 inhibition and . Mechanistically, loss resulted in exclusion of p27 from the nucleus, leading to increased activation of both CDK4 and CDK2. Because loss also causes resistance to PI3Kα inhibitors, currently approved in the post-CDK4/6 setting, these findings provide critical insight into how this single genetic event may cause clinical cross-resistance to multiple targeted therapies in the same patient, with implications for optimal treatment-sequencing strategies. SIGNIFICANCE: Our analysis of serial biopsies uncovered RB and PTEN loss as mechanisms of acquired resistance to CDK4/6 inhibitors, utilized as first-line treatment for ER-positive advanced breast cancer. Importantly, these findings have near-term clinical relevance because loss also limits the efficacy of PI3Kα inhibitors currently approved in the post-CDK4/6 setting..
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http://dx.doi.org/10.1158/2159-8290.CD-18-0830DOI Listing
January 2020

Response to Anti-EGFR Therapy in Patients with BRAF non-V600-Mutant Metastatic Colorectal Cancer.

Clin Cancer Res 2019 12 12;25(23):7089-7097. Epub 2019 Sep 12.

Division of Molecular Therapeutics, Aichi Cancer Center Research Institute, Nagoya, Aichi, Japan.

Purpose: While mutations in BRAF in metastatic colorectal cancer (mCRC) most commonly occur at the V600 amino acid, with the advent of next-generation sequencing, non-V600 BRAF mutations are increasingly identified in clinical practice. It is unclear whether these mutants, like BRAF V600E, confer resistance to anti-EGFR therapy.

Experimental Design: We conducted a multicenter pooled analysis of consecutive patients with non-V600 BRAF-mutated mCRCs identified between 2010 and 2017. Non-V600 BRAF mutations were divided into functional classes based on signaling mechanism and kinase activity: activating and RAS-independent (class 2) or kinase-impaired and RAS-dependent (class 3).

Results: Forty patients with oncogenic non-V600 BRAF-mutant mCRC received anti-EGFR antibody treatment [ = 12 (30%) class 2 and = 28 (70%) class 3]. No significant differences in clinical characteristics were observed by mutation class. In contrast, while only 1 of 12 patients with class 2 BRAF mCRC responded, 14 of 28 patients with class 3 BRAF responded to anti-EGFR therapy (response rate, 8% and 50%, respectively, = 0.02). Specifically, in first- or second-line, 1 of 6 (17%) patients with class 2 and 7 of 9 (78%) patients with class 3 BRAF mutants responded ( = 0.04). In third- or later-line, none of 6 patients with class 2 and 7 of 19 (37%) patients with class 3 BRAF mutants responded ( = 0.14).

Conclusions: Response to EGFR antibody treatment in mCRCs with class 2 BRAF mutants is rare, while a large portion of CRCs with class 3 BRAF mutants respond. Patients with colorectal cancer with class 3 BRAF mutations should be considered for anti-EGFR antibody treatment..
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http://dx.doi.org/10.1158/1078-0432.CCR-19-2004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6891165PMC
December 2019

The ADAM17 protease promotes tobacco smoke carcinogen-induced lung tumorigenesis.

Carcinogenesis 2020 06;41(4):527-538

Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.

Lung cancer is the leading cause of cancer-related mortality, with most cases attributed to tobacco smoking, in which nicotine-derived nitrosamine ketone (NNK) is the most potent lung carcinogen. The ADAM17 protease is responsible for the ectodomain shedding of many pro-tumorigenic cytokines, growth factors and receptors, and therefore is an attractive target in cancer. However, the role of ADAM17 in promoting tobacco smoke carcinogen-induced lung carcinogenesis is unknown. The hypomorphic Adam17ex/ex mice-characterized by reduced global ADAM17 expression-were backcrossed onto the NNK-sensitive pseudo-A/J background. CRISPR-driven and inhibitor-based (GW280264X, and ADAM17 prodomain) ADAM17 targeting was employed in the human lung adenocarcinoma cell lines A549 and NCI-H23. Human lung cancer biopsies were also used for analyses. The Adam17ex/ex mice displayed marked protection against NNK-induced lung adenocarcinoma. Specifically, the number and size of lung lesions in NNK-treated pseudo-A/J Adam17ex/ex mice were significantly reduced compared with wild-type littermate controls. This was associated with lower proliferative index throughout the lung epithelium. ADAM17 targeting in A549 and NCI-H23 cells led to reduced proliferative and colony-forming capacities. Notably, among select ADAM17 substrates, ADAM17 deficiency abrogated shedding of the soluble IL-6 receptor (sIL-6R), which coincided with the blockade of sIL-6R-mediated trans-signaling via ERK MAPK cascade. Furthermore, NNK upregulated phosphorylation of p38 MAPK, whose pharmacological inhibition suppressed ADAM17 threonine phosphorylation. Importantly, ADAM17 threonine phosphorylation was significantly upregulated in human lung adenocarcinoma with smoking history compared with their cancer-free controls. Our study identifies the ADAM17/sIL-6R/ERK MAPK axis as a candidate therapeutic strategy against tobacco smoke-associated lung carcinogenesis.
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http://dx.doi.org/10.1093/carcin/bgz123DOI Listing
June 2020

ADAM17 selectively activates the IL-6 trans-signaling/ERK MAPK axis in KRAS-addicted lung cancer.

EMBO Mol Med 2019 04;11(4)

Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Vic., Australia

Oncogenic mutations are major drivers of lung adenocarcinoma (LAC), yet the direct therapeutic targeting of KRAS has been problematic. Here, we reveal an obligate requirement by oncogenic KRAS for the ADAM17 protease in LAC In genetically engineered and xenograft (human cell line and patient-derived) -driven LAC models, the specific blockade of ADAM17, including with a non-toxic prodomain inhibitor, suppressed tumor burden by reducing cellular proliferation. The pro-tumorigenic activity of ADAM17 was dependent upon its threonine phosphorylation by p38 MAPK, along with the preferential shedding of the ADAM17 substrate, IL-6R, to release soluble IL-6R that drives IL-6 trans-signaling via the ERK1/2 MAPK pathway. The requirement for ADAM17 in -driven LAC was independent of bone marrow-derived immune cells. Furthermore, in mutant human LAC, there was a significant positive correlation between augmented phospho-ADAM17 levels, observed primarily in epithelial rather than immune cells, and activation of ERK and p38 MAPK pathways. Collectively, these findings identify ADAM17 as a druggable target for oncogenic -driven LAC and provide the rationale to employ ADAM17-based therapeutic strategies for targeting mutant cancers.
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http://dx.doi.org/10.15252/emmm.201809976DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6460353PMC
April 2019

Anaplastic lymphoma kinase expression in small-cell lung cancer.

Histopathology 2019 Jul 23;75(1):20-28. Epub 2019 May 23.

Department of Pathology and Molecular Diagnostics, Aichi Cancer Centre, Nagoya, Japan.

Aims: Anaplastic lymphoma kinase (ALK) immunohistochemistry has shifted from being a screening tool to being a sole determinant for ALK-targeted therapy. Recent articles have referred to small-cell lung cancer (SCLC) transformation as a resistance mechanism after ALK inhibitor treatments, but few reports have addressed ALK expression in treatment-naive SCLC in a comprehensive manner. Therefore, we examined ALK expression and the mechanisms in treatment-naive SCLCs.

Methods And Results: We examined ALK expression in a consecutive series of SCLC tumours, and the expression mechanism was analysed regarding gene rearrangement, copy number changes, and point mutations. We also examined whether SCLC with ALK expression can be suppressed by crizotinib treatment in vitro. Immunohistochemical results revealed that ALK was expressed in 16 of 142 (11.3%) SCLCs. The expression was focal and less intense, which is in contrast to strong and uniform expression in adenocarcinoma with ALK rearrangement. Two combined SCLCs showed a positive reaction restricted to the SCLC component. None of the known genetic alterations, including rearrangement, amplification, copy number gain, or point mutations, were associated with ALK expression. A SCLC cell line, SKLC2, which expressed ALK without known genetic alterations, was not inhibited by a practically achievable serum concentration of crizotinib.

Conclusions: Anaplastic lymphoma kinase immunohistochemistry for treatment-naive SCLCs should not be used as a predictive biomarker for ALK inhibitor therapy, because the positive reactions were due to intrinsic expression of normal ALK transcript.
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http://dx.doi.org/10.1111/his.13842DOI Listing
July 2019

Pulmonary carcinosarcoma showing an obvious response to pazopanib: a case report.

BMC Pulm Med 2018 Dec 12;18(1):193. Epub 2018 Dec 12.

Division of Medical Oncology, Cancer Research Institute, Kanazawa University, 13-1, Takara-machi, Kanazawa, Ishikawa, 920-0934, Japan.

Background: Pulmonary carcinosarcoma (PCS) is a rare primary lung malignancy and has a poor prognosis among lung tumor histological subtypes. However, an appropriate treatment strategy has not been developed for unresectable PCS.

Case Presentation: A 65-year-old man who was diagnosed with PCS was treated by surgical removal of the primary lung lesion, followed by six cycles of adjuvant chemotherapy with cisplatin plus irinotecan. Following the chemotherapy, he experienced a relapse with brain metastasis, which induced the rapid onset of left leg paralysis. Radical surgical resection and stereotactic radiosurgery to the resection cavity were performed. However, meningeal dissemination and new lung metastases occurred after a year and half. To control these multiple metastatic lesions, the patient was treated with the multiple kinase inhibitor pazopanib. No change was observed in the meningeal dissemination, while the metastatic lung lesions were prominently reduced in size following treatment with pazopanib. Consequently, the patient showed a partial response to pazopanib treatment, although the dose of pazopanib was reduced by half as a result of thrombocytopenia.

Conclusion: This is the first report of metastatic PCS showing an evident therapeutic response to tumor-targeted therapy. We suggest that pazopanib may be a therapeutic option for patients with metastatic PCS.
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http://dx.doi.org/10.1186/s12890-018-0757-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6291996PMC
December 2018

Increased Synthesis of MCL-1 Protein Underlies Initial Survival of -Mutant Lung Cancer to EGFR Inhibitors and Provides a Novel Drug Target.

Clin Cancer Res 2018 11 7;24(22):5658-5672. Epub 2018 Aug 7.

Philips Institute for Oral Health Research, VCU School of Dentistry and Massey Cancer Center, Richmond, Virginia.

EGFR inhibitors (EGFRi) are effective against -mutant lung cancers. The efficacy of these drugs, however, is mitigated by the outgrowth of resistant cells, most often driven by a secondary acquired mutation in EGFR, We recently demonstrated that can arise during treatment; it follows that one potential therapeutic strategy to thwart resistance would be identifying and eliminating these cells [referred to as drug-tolerant cells (DTC)] prior to acquiring secondary mutations like We have developed DTCs to EGFRi in -mutant lung cancer cell lines. Subsequent analyses of DTCs included RNA-seq, high-content microscopy, and protein translational assays. Based on these results, we tested the ability of MCL-1 BH3 mimetics to combine with EGFR inhibitors to eliminate DTCs and shrink -mutant lung cancer tumors We demonstrate surviving -mutant lung cancer cells upregulate the antiapoptotic protein MCL-1 in response to short-term EGFRi treatment. Mechanistically, DTCs undergo a protein biosynthesis enrichment resulting in increased mTORC1-mediated mRNA translation of MCL-1, revealing a novel mechanism in which lung cancer cells adapt to short-term pressures of apoptosis-inducing kinase inhibitors. Moreover, MCL-1 is a key molecule governing the emergence of early -mutant DTCs to EGFRi, and we demonstrate it can be effectively cotargeted with clinically emerging MCL-1 inhibitors both and Altogether, these data reveal that this novel therapeutic combination may delay the acquisition of secondary mutations, therefore prolonging therapy efficacy. .
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http://dx.doi.org/10.1158/1078-0432.CCR-18-0304DOI Listing
November 2018

[Successful Long-Term Treatment with Intermittent Oxaliplatin Administration for Recurrent Sigmoid Colon Cancer without Developing Neuropathy].

Gan To Kagaku Ryoho 2018 Jul;45(7):1113-1116

Dept. of Pharmacy, Houju Memorial Hospital.

We report a case ofrecurrent sigmoid cancer in which long-term disease control was achieved by intermittent oxaliplatin (L-OHP)administration. A 58-year-old woman underwent first-line chemotherapy with capecitabine and L-OHP(CapeOX) following peritoneal lymph node recurrence of sigmoid cancer. Tumor shrinkage was confirmed by a computed tomography (CT)scan following 4 courses of CapeOX treatment. However, L-OHP administration was discontinued by the 9 course due to peritoneal neuropathy. L-OHP was reintroduced following tumor progression confirmed by CT or elevation of carcinoembryonic antigen levels detected by a blood test. This stop-and-go strategy controlled lymph node recurrence effectively for over 5 years and was not associated with the development ofperitoneal neuropathy. We suggest that the intermittent administration ofL -OHP-containing chemotherapy is an important treatment option for some patients with advanced colorectal cancer, achieving effective long-term disease control with no associated peripheral neuropathy.
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July 2018

Japanese Society of Medical Oncology Clinical Guidelines: Molecular Testing for Colorectal Cancer Treatment, Third Edition.

Cancer Sci 2018 Jun;109(6):2074-2079

Division of Translational Research, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Chiba, Japan.

The Japanese Society of Medical Oncology (JSMO) previously published 2 editions of the clinical guidelines: "Japanese guidelines for testing of KRAS gene mutation in colorectal cancer" in 2008 and "Japanese Society of Medical Oncology Clinical Guidelines: RAS (KRAS/NRAS) mutation testing in colorectal cancer patients" in 2014. These guidelines have contributed to the proper use of KRAS and RAS mutation testing, respectively. Recently, clinical utility, particularly for colorectal cancer (CRC) patients with BRAF V600E mutation or DNA mismatch-repair (MMR) deficiency, has been established. Therefore, the guideline members decided these genetic alterations should also be involved. The aim of this revision is to properly carry out testing for BRAF V600E mutation and MMR deficiency in addition to RAS mutation. The revised guidelines include the basic requirements for testing for these genetic alterations based on recent scientific evidence. Furthermore, because clinical utility of comprehensive genetic testing using next-generation sequencing and somatic gene testing of analyzing circulating tumor DNA has increasingly evolved with recent advancements in testing technology, we noted the current situation and prospects for these testing technologies and their clinical implementation in the revised guidelines.
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http://dx.doi.org/10.1111/cas.13617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5989850PMC
June 2018

Distinct dependencies on receptor tyrosine kinases in the regulation of MAPK signaling between BRAF V600E and non-V600E mutant lung cancers.

Oncogene 2018 03 19;37(13):1775-1787. Epub 2018 Jan 19.

Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Ishikawa, Japan.

BRAF is one of the most frequently mutated genes across a number of different cancers, with the best-characterized mutation being V600E. Despite the successes of treating BRAF mutant V600E lung cancer with BRAF pathway inhibitors, treatment strategies targeting tumors with non-V600E mutations are yet to be established. We studied cellular signaling differences between lung cancers with different BRAF mutations and determined their sensitivities to BRAF pathway inhibitors. Here, we observed that MEK inhibition induced feedback activation of the receptor tyrosine kinase (RTK) EGFR, and in some cases the RTK FGFR, resulting in transient suppression of ERK phosphorylation in BRAF non-V600E, but not BRAF V600E, mutant cells. Furthermore, we found that both EGFR and FGFR activated the MEK/ERK pathway, despite the presence of BRAF non-V600E mutations with elevated kinase activity. Moreover, in BRAF non-V600E mutants with impaired kinase activities, EGFR had even greater control over the MEK/ERK pathway, essentially contributing completely to the tonic mitogen-activated protein kinase (MAPK) signal. Accordingly, the combination of MEK inhibitor with EGFR inhibitor was effective at shrinking tumors in mouse model of BRAF non-V600E mutant lung cancer. Furthermore, the results were recapitulated with a clinically relevant dual inhibitor of EGFR and RAF, BGB-283. Overall, although BRAF V600E mutant cells are sensitive to BRAF inhibition, non-V600E mutant cancer cells are reliant on RTKs for their MAPK activation and inhibiting both MEK and RTKs are necessary in these cancers. Our findings provide evidence of critical survival signals in BRAF non-V600E mutant cancers, which could pave the way for effective treatment of these cancers.
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http://dx.doi.org/10.1038/s41388-017-0035-9DOI Listing
March 2018

Epithelial-to-Mesenchymal Transition Antagonizes Response to Targeted Therapies in Lung Cancer by Suppressing BIM.

Clin Cancer Res 2018 01 19;24(1):197-208. Epub 2017 Oct 19.

Philips Institute for Oral Health Research, VCU School of Dentistry and Massey Cancer Center, Richmond, Virginia.

Epithelial-to-mesenchymal transition (EMT) confers resistance to a number of targeted therapies and chemotherapies. However, it has been unclear why EMT promotes resistance, thereby impairing progress to overcome it. We have developed several models of EMT-mediated resistance to EGFR inhibitors (EGFRi) in -mutant lung cancers to evaluate a novel mechanism of EMT-mediated resistance. We observed that mesenchymal -mutant lung cancers are resistant to EGFRi-induced apoptosis via insufficient expression of BIM, preventing cell death despite potent suppression of oncogenic signaling following EGFRi treatment. Mechanistically, we observed that the EMT transcription factor ZEB1 inhibits BIM expression by binding directly to the BIM promoter and repressing transcription. Derepression of BIM expression by depletion of ZEB1 or treatment with the BH3 mimetic ABT-263 to enhance "free" cellular BIM levels both led to resensitization of mesenchymal -mutant cancers to EGFRi. This relationship between EMT and loss of BIM is not restricted to -mutant lung cancers, as it was also observed in -mutant lung cancers and large datasets, including different cancer subtypes. Altogether, these data reveal a novel mechanistic link between EMT and resistance to lung cancer targeted therapies. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-1577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5959009PMC
January 2018

Resistance mediated by alternative receptor tyrosine kinases in FGFR1-amplified lung cancer.

Carcinogenesis 2017 10;38(11):1063-1072

Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Ishikawa 920-0934, Japan.

Fibroblast growth factor receptor 1 (FGFR1) amplification has been identified in 10-20% of patients with squamous non-small-cell lung cancer. Preclinical models showed promising activity of specific FGFR inhibitors, but early clinical trials showed that only a small fraction of patients with FGFR1-amplified lung cancer responded to FGFR inhibitors. These unsatisfactory results were partly explained by heterogeneous amplicons around the 8p11 genomic region, leading to false-positive amplification results. Furthermore, discrepancies in the gene amplification and protein expression of FGFR1 were also reported. In this study, we identified the roles of alternative receptor tyrosine kinases (RTKs) in FGFR1-amplified lung cancer. These alternative RTKs dominantly activate phosphoinositide 3-kinase-AKT signaling and also mitigate sustained inhibition of mitogen-activated protein kinase signaling by FGFR inhibitors. The rebound activation of extracellular signal-regulated kinase phosphorylation was associated with sensitivity to the drugs. Combinatorial inhibition of alternative RTKs and FGFR1 was required to suppress both AKT and extracellular signal-regulated kinase phosphorylation and to induce key pro-apoptotic proteins BIM and p53 upregulated modulator of apoptosis (PUMA). Furthermore, even in FGFR inhibitor-sensitive NCI-H1581 lung cancer cells, MET-expressing clones were already detectable at a very low frequency before resistance induction. Selection of these pre-existing subclones resulted in FGFR inhibitor resistance because of the activation of AKT and extracellular signal-regulated kinase by MET signaling that was mediated by GRB2 associated binding protein 1 (GAB1). These results suggest that incomplete suppression of key survival signals led to intrinsic and acquired resistance to FGFR inhibitors. Our results may help explain the low clinical response rates to FGFR inhibitors in FGFR1-amplified lung cancer.
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http://dx.doi.org/10.1093/carcin/bgx091DOI Listing
October 2017

A systematic review and meta-analysis of individual patient data on the impact of the BIM deletion polymorphism on treatment outcomes in epidermal growth factor receptor mutant lung cancer.

Oncotarget 2017 Jun;8(25):41474-41486

Division of Medical Oncology, National Cancer Centre, Singapore.

Background: A germline deletion in the BIM (BCL2L11) gene has been shown to impair the apoptotic response to tyrosine kinase inhibitors (TKIs) in vitro but its association with poor outcomes in TKI-treated non-small cell lung cancer (NSCLC) patients remains unclear. We conducted a systematic review and meta-analysis on both aggregate and individual patient data to address this issue.

Results: In an aggregate data meta-analysis (n = 1429), the BIM deletion was associated with inferior PFS (HR = 1.51, 95%CI = 1.06-2.13, P = 0.02). Using individual patient data (n = 1200), we found a significant interaction between the deletion and ethnicity. Amongst non-Koreans, the deletion was an independent predictor of shorter PFS (Chinese: HR = 1.607, 95%CI = 1.251-2.065, P = 0.0002; Japanese: HR = 2.636, 95%CI = 1.603-4.335, P = 0.0001), and OS (HR = 1.457, 95% CI = 1.063-1.997, P = 0.019). In Kaplan-Meier analyses, the BIM deletion was associated with shorter survival in non-Koreans (PFS: 8.0 months v 11.1 months, P < 0.0005; OS: 25.7 v 30.0 months, P = 0.042). In Koreans, the BIM deletion was not predictive of PFS or OS.

Materials And Methods: 10 published and 3 unpublished studies that reported survival outcomes in NSCLC patients stratified according to BIM deletion were identified from PubMed and Embase. Summary risk estimates were calculated from aggregate patient data using a random-effects model. For individual patient data, Kaplan-Meier analyses were supported by multivariate Cox regression to estimate hazard ratios (HRs) for PFS and OS.

Conclusions: In selected populations, the BIM deletion is a significant predictor of shorter PFS and OS on EGFR-TKIs. Further studies to determine its effect on response to other BIM-dependent therapeutic agents are needed, so that alternative treatment strategies may be devised.
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http://dx.doi.org/10.18632/oncotarget.17102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5522319PMC
June 2017

Key roles of EMT for adaptive resistance to MEK inhibitor in KRAS mutant lung cancer.

Small GTPases 2017 07 8;8(3):172-176. Epub 2016 Jul 8.

a Division of Medical Oncology , Cancer Research Institute, Kanazawa University , Ishikawa , Japan.

KRAS is frequently mutated in a variety of cancers including lung cancer. Whereas the mitogen-activated protein kinase (MAPK) is a well-known effector pathway of KRAS, blocking this pathway with MEK inhibitors is relatively ineffective. One major contributor to limited efficacy is attributed to the reactivation of MAPK signal following MEK inhibition by multiple feedback mechanisms. In a recent study, we have identified that epithelial-to-mesenchymal transition defines feedback activation of receptor tyrosine kinase signaling following MEK inhibition in KRAS mutant lung cancer. In epithelial-like cells, this feedback was mediated by ERBB3. In contrast, in mesenchymal-like cells, the feedback was attributed to the fibroblast growth factor receptor 1 (FGFR1) pathway. FGFR1 was dominantly expressed in mesenchymal-like cells: suppression of SPRY proteins by MEK inhibition relieved negative feedback control of basal FGFR-FRS2 function, resulting in reactivation of MAPK signaling via FGFR1. Therapeutically, the combination of MEK inhibitor trametinib with an FGFR inhibitor induced tumor regressions in tumor xenografts derived from mesenchymal-like KRAS mutant cancer cell lines as well as a patient derived xenograft model with a representative mesenchymal phenotype. Collectively, feedback activation of MAPK by FGFR1 signaling mitigates the effect of MEK inhibitor in mesenchymal-like KRAS mutant lung tumors, and combinations of clinically available FGFR1 inhibitors and MAPK inhibitors constitute a therapeutic approach to treat these cancers effectively.
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http://dx.doi.org/10.1080/21541248.2016.1210369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5584737PMC
July 2017

Epithelial-to-Mesenchymal Transition Defines Feedback Activation of Receptor Tyrosine Kinase Signaling Induced by MEK Inhibition in KRAS-Mutant Lung Cancer.

Cancer Discov 2016 07 6;6(7):754-69. Epub 2016 May 6.

Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Ishikawa, Japan.

Unlabelled: KRAS is frequently mutated in lung cancer. Whereas MAPK is a well-known effector pathway of KRAS, blocking this pathway with clinically available MAPK inhibitors is relatively ineffective. Here, we report that epithelial-to-mesenchymal transition rewires the expression of receptor tyrosine kinases, leading to differential feedback activation of the MAPK pathway following MEK inhibition. In epithelial-like KRAS-mutant lung cancers, this feedback was attributed to ERBB3-mediated activation of MEK and AKT. In contrast, in mesenchymal-like KRAS-mutant lung cancers, FGFR1 was dominantly expressed but suppressed by the negative regulator Sprouty proteins; MEK inhibition led to repression of SPRY4 and subsequent FGFR1-mediated reactivation of MEK and AKT. Therapeutically, the combination of a MEK inhibitor (MEKi) and an FGFR inhibitor (FGFRi) induced cell death in vitro and tumor regressions in vivo These data establish the rationale and a therapeutic approach to treat mesenchymal-like KRAS-mutant lung cancers effectively with clinically available FGFR1 and MAPK inhibitors.

Significance: Adaptive resistance to MEKi is driven by receptor tyrosine kinases specific to the differentiation state of the KRAS-mutant non-small cell lung cancer (NSCLC). In mesenchymal-like KRAS-mutant NSCLC, FGFR1 is highly expressed, and MEK inhibition relieves feedback suppression of FGFR1, resulting in reactivation of ERK; suppression of ERK by MEKi/FGFRi combination results in tumor shrinkage. Cancer Discov; 6(7); 754-69. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 681.
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http://dx.doi.org/10.1158/2159-8290.CD-15-1377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4957999PMC
July 2016

Recurrence of renal cell carcinoma diagnosed using contralateral adrenal biopsy with endoscopic ultrasound-guided fine-needle aspiration.

Mol Clin Oncol 2016 Apr 25;4(4):537-540. Epub 2016 Jan 25.

Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-0934, Japan.

A 76-year-old female in whom a renal cell carcinoma (RCC) lesion was resected 19 years previously presented to our hospital with cognitive dysfunction. Magnetic resonance imaging and computed tomography revealed nodules in the brain, lung, adrenal gland and a pelvic osteolytic lesion. To identify the primary cancer site, the present study performed endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) of the left adrenal lesion. Consequently, the pathological findings of the tissue obtained by EUS-FNA were similar to those of the previous nephrectomy specimen, revealing that the adrenal lesion was the recurrence of RCC. The majority of the metastatic lesions in the patient were reduced in size by the multiple kinase inhibitor, pazopanib. Contralateral adrenal metastasis of RCC is rare and the use of EUS-FNA in the diagnosis of adrenal lesions remains to be elucidated. This is a rare case of adrenal lesion, diagnosed by EUS-FNA. Therefore, EUS-FNA is considered to be a useful diagnostic modality of adrenal metastases from unidentified primary tumor types.
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http://dx.doi.org/10.3892/mco.2016.739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4812346PMC
April 2016

High efficacy of third generation EGFR inhibitor AZD9291 in a leptomeningeal carcinomatosis model with EGFR-mutant lung cancer cells.

Oncotarget 2016 Jan;7(4):3847-56

Department of Medical Oncology, Kanazawa University Cancer Research Institute, Kanazawa, Japan.

Leptomeningeal carcinomatosis (LMC) remarkably decreases the quality of life of EGFR-mutant lung cancer patients. In contrast to the lesions outside the central nervous system (CNS), molecular mechanisms of EGFR tyrosine kinase inhibitor (TKI) resistance in CNS lesions including LMC are largely unknown. In this study, we established an in vivo imaging model for LMC with EGFR mutant lung cancer cell lines harboring an exon 19 deletion in EGFR and evaluated the effect of first generation EGFR-TKIs, erlotinib, second generation afatinib, and third generation AZD9291. In PC-9/ffluc model, erlotinib treatment slowed the development of LMC. Importantly, treatment with afatinib or AZD9291 apparently delayed the development of LMC. Moreover, treatment with a higher dose of AZD9291, also associated with inhibited phosphorylation of EGFR downstream molecule S6, regressed LMC refractory to the aforementioned EGFR-TKI treatments. These observations suggest that the third generation EGFR-TKI AZD9291 may be an effective treatment for first or second generation EGFR-TKI resistant LMC caused by EGFR-mutant lung cancer.
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http://dx.doi.org/10.18632/oncotarget.6758DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4826174PMC
January 2016

Japanese Society of Medical Oncology Clinical Guidelines: RAS (KRAS/NRAS) mutation testing in colorectal cancer patients.

Cancer Sci 2015 Mar;106(3):324-7

Department of Clinical Oncology, Aichi Cancer Center Hospital, Aichi, Japan.

The Japanese guidelines for the testing of KRAS mutations in colorectal cancer have been used for the past 5 years. However, new findings of RAS (KRAS/NRAS) mutations that can further predict the therapeutic effects of anti-epidermal growth factor receptor (EGFR) antibody therapy necessitated a revision of the guidelines. The revised guidelines included the following five basic requirements for RAS mutation testing to highlight a patient group in which anti-EGFR antibody therapy may be ineffective: First, anti-EGFR antibody therapy may not offer survival benefit and/or tumor shrinkage to patients with expanded RAS mutations. Thus, current methods to detect KRAS exon 2 (codons 12 and 13) mutations are insufficient for selecting appropriate candidates for this therapy. Additional testing of extended KRAS/NRAS mutations is recommended. Second, repeated tests are not required for the detection; tissue materials of either primary or metastatic lesions are applicable for RAS mutation testing. Evaluating RAS mutations prior to anti-EGFR antibody therapy is recommended. Third, direct sequencing with manual dissection or allele-specific PCR-based methods is currently applicable for RAS mutation testing. Fourth, thinly sliced sections of formalin-fixed, paraffin-embedded tissue blocks are applicable for RAS mutation testing. One section stained with H&E should be provided to histologically determine whether the tissue contains sufficient amount of tumor cells for testing. Finally, RAS mutation testing must be performed in laboratories with appropriate testing procedures and specimen management practices.
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http://dx.doi.org/10.1111/cas.12595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4376442PMC
March 2015

Assessment of ABT-263 activity across a cancer cell line collection leads to a potent combination therapy for small-cell lung cancer.

Proc Natl Acad Sci U S A 2015 Mar 3;112(11):E1288-96. Epub 2015 Mar 3.

Massachusetts General Hospital Cancer Center, Boston, MA 02129; Department of Medicine, Harvard Medical School, Boston, MA 02115;

BH3 mimetics such as ABT-263 induce apoptosis in a subset of cancer models. However, these drugs have shown limited clinical efficacy as single agents in small-cell lung cancer (SCLC) and other solid tumor malignancies, and rational combination strategies remain underexplored. To develop a novel therapeutic approach, we examined the efficacy of ABT-263 across >500 cancer cell lines, including 311 for which we had matched expression data for select genes. We found that high expression of the proapoptotic gene Bcl2-interacting mediator of cell death (BIM) predicts sensitivity to ABT-263. In particular, SCLC cell lines possessed greater BIM transcript levels than most other solid tumors and are among the most sensitive to ABT-263. However, a subset of relatively resistant SCLC cell lines has concomitant high expression of the antiapoptotic myeloid cell leukemia 1 (MCL-1). Whereas ABT-263 released BIM from complexes with BCL-2 and BCL-XL, high expression of MCL-1 sequestered BIM released from BCL-2 and BCL-XL, thereby abrogating apoptosis. We found that SCLCs were sensitized to ABT-263 via TORC1/2 inhibition, which led to reduced MCL-1 protein levels, thereby facilitating BIM-mediated apoptosis. AZD8055 and ABT-263 together induced marked apoptosis in vitro, as well as tumor regressions in multiple SCLC xenograft models. In a Tp53; Rb1 deletion genetically engineered mouse model of SCLC, the combination of ABT-263 and AZD8055 significantly repressed tumor growth and induced tumor regressions compared with either drug alone. Furthermore, in a SCLC patient-derived xenograft model that was resistant to ABT-263 alone, the addition of AZD8055 induced potent tumor regression. Therefore, addition of a TORC1/2 inhibitor offers a therapeutic strategy to markedly improve ABT-263 activity in SCLC.
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http://dx.doi.org/10.1073/pnas.1411848112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4371986PMC
March 2015

Measurement of PIP3 levels reveals an unexpected role for p110β in early adaptive responses to p110α-specific inhibitors in luminal breast cancer.

Cancer Cell 2015 Jan 24;27(1):97-108. Epub 2014 Dec 24.

Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA. Electronic address:

BYL719, which selectively inhibits the alpha isoform of the phosphatidylinositol 3-kinase (PI3K) catalytic subunit (p110a), is currently in clinical trials for the treatment of solid tumors, especially luminal breast cancers with PIK3CA mutations and/or HER2 amplification. This study reveals that, even among these sensitive cancers, the initial efficacy of p110α inhibition is mitigated by rapid re-accumulation of the PI3K product PIP3 produced by the p110β isoform. Importantly, the reactivation of PI3K mediated by p110β does not invariably restore AKT phosphorylation, demonstrating the limitations of using phospho-AKT as a surrogate to measure PI3K activation. Consistently, we show that the addition of the p110β inhibitor to BYL719 prevents the PIP3 rebound and induces greater antitumor efficacy in HER2-amplified and PIK3CA mutant cancers.
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http://dx.doi.org/10.1016/j.ccell.2014.11.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4745884PMC
January 2015

Lack of association between the BIM deletion polymorphism and the risk of lung cancer with and without EGFR mutations.

J Thorac Oncol 2015 Jan;10(1):59-66

*Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan; †Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Aichi, Japan; ‡Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan; §Thoracic Surgery, Aichi Cancer Center Hospital, Aichi, Japan; ‖Department of Thoracic Oncology, Aichi Cancer Center Hospital, Aichi, Japan; ¶VCU Philips Institute for Oral Health Research, School of Dentistry and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA; #Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, Aichi, Japan; **Department of Surgery, Division of Thoracic Surgery, Kinki University Faculty of Medicine, Osaka-Sayama, Japan; and ††Department of Preventive Medicine, Kyushu University Faculty of Medical Sciences, Fukuoka, Japan.

Introduction: The BIM deletion polymorphism in intron 2 was found in a significant percent of the Asian population. Patients with epidermal growth factor receptor (EGFR) mutant lung cancers harboring this BIM polymorphism have shorter progression free survival and overall response rates to EGFR tyrosine kinase inhibitors. However, the association between the BIM deletion polymorphism and lung cancer risk is unknown.

Methods: The BIM deletion polymorphism was screened by polymerase chain reaction in 765 lung cancer cases and 942 healthy individuals.

Results: Carriers possessing one allele of the BIM polymorphism were observed in 13.0% of control cases and 12.8% of lung cancer cases, similar to incidence rates reported earlier in healthy individuals. Homozygote for the BIM polymorphism was observed in four of 942 healthy controls and three of 765 lung cancer cases. The frequency of the BIM deletion polymorphism in lung cancer patients was not related to age, sex, smoking history, or family history of lung cancer. The BIM deletion polymorphism was found in 30 of 212 patients with EGFR wild type lung cancers and 16 of 120 patients with EGFR mutant lung cancers. The frequency of the BIM polymorphism is similar between cancers with wild type EGFR and mutated EGFR (p = 0.78).

Conclusion: The BIM deletion polymorphism was not associated with lung cancer susceptibility. Furthermore, the BIM polymorphism is not associated with EGFR mutant lung cancer.
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http://dx.doi.org/10.1097/JTO.0000000000000371DOI Listing
January 2015