Publications by authors named "Susumu S Kobayashi"

40 Publications

Single-Cell Analyses Reveal Diverse Mechanisms of Resistance to EGFR Tyrosine Kinase Inhibitors in Lung Cancer.

Cancer Res 2021 Sep 9;81(18):4835-4848. Epub 2021 Jul 9.

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

Tumor heterogeneity underlies resistance to tyrosine kinase inhibitors (TKI) in lung cancers harboring mutations. Previous evidence suggested that subsets of preexisting resistant cells are selected by EGFR-TKI treatment, or alternatively, that diverse acquired resistance mechanisms emerge from drug-tolerant persister (DTP) cells. Many studies have used bulk tumor specimens or subcloned resistant cell lines to identify resistance mechanism. However, intratumoral heterogeneity can result in divergent responses to therapies, requiring additional approaches to reveal the complete spectrum of resistance mechanisms. Using EGFR-TKI-resistant cell models and clinical specimens, we performed single-cell RNA-seq and single-cell ATAC-seq analyses to define the transcriptional and epigenetic landscape of parental cells, DTPs, and tumor cells in a fully resistant state. In addition to , , and , which are all known to induce EGFR-TKI resistance, was identified as a novel gene that plays a critical role in the drug-tolerant state. and experiments demonstrated that CD74 upregulation confers resistance to the EGFR-TKI osimertinib and blocks apoptosis, enabling tumor regrowth. Overall, this study provides new insight into the mechanisms underlying resistance to EGFR-TKIs. SIGNIFICANCE: Single-cell analyses identify diverse mechanisms of resistance as well as the state of tolerant cells that give rise to resistance to EGFR tyrosine kinase inhibitors.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-2811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8448980PMC
September 2021

EGFR-A763_Y764insFQEA Is a Unique Exon 20 Insertion Mutation That Displays Sensitivity to Approved and In-Development Lung Cancer EGFR Tyrosine Kinase Inhibitors.

JTO Clin Res Rep 2020 Sep 13;1(3). Epub 2020 May 13.

Department of Medicine, Division of Medical Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.

Introduction: The EGFR-A763_Y764insFQEA is a unique exon 20 insertion mutation (~5% to 6% of exon 20 insertions), which, at the structural and enzyme kinetic level, more closely resembles EGFR tyrosine kinase inhibitor (TKI)- sensitizing mutants, such as EGFR exon 19 indels and L858R. A limited number of preclinical models and clinical reports have studied the response of this mutant to EGFR TKIs.

Methods: We used models of EGFR-A763_Y764insFQEA and more typical EGFR exon 20 insertion mutations to probe representative first- (gefitinib, erlotinib), second- (afatinib), third-generation (osimertinib), and in-development EGFR exon 20-specific (poziotinib, mobocertinib [TAK-788]) TKIs. We also compiled outcomes of -A763_Y764insFQEA-mutated lung cancers treated with EGFR TKIs.

Results: Cells driven by EGFR-A763_Y764insFQEA were consistently sensitive to EGFR TKIs (as opposed to those driven by typical EGFR exon 20 insertions [A767_V769dupASV, D770_N771insSVD and H773_V774insH]), which were only inhibited by in-development EGFR TKIs at doses below those affecting wild-type EGFR. Most case instances (62.5% [95% confidence interval: 39%-86%], n = 16) with lung cancers harboring EGFR-A763_Y764insFQEA responded to clinically available EGFR TKIs (including osimertinib) and to in-development EGFR exon 20-specific TKIs (including mobocertinib) with prolonged periods of progression-free survival in some cases. Median overall survival for EGFR TKI-treated cases was 22 months (95% confidence interval: 16-25). Mechanisms of acquired TKI resistance of this mutant remain underreported, but do seem to align with those of common mutations.

Conclusions: To our knowledge, this is the largest report to confirm that the EGFR-A763_Y764insFQEA mutation is sensitive to clinically available first-, second-, third-generation, and in-development EGFR TKIs.
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http://dx.doi.org/10.1016/j.jtocrr.2020.100051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8183979PMC
September 2020

Upregulation of FGF9 in Lung Adenocarcinoma Transdifferentiation to Small Cell Lung Cancer.

Cancer Res 2021 Jul 3;81(14):3916-3929. Epub 2021 Jun 3.

Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan.

Transdifferentiation of lung adenocarcinoma to small cell lung cancer (SCLC) has been reported in a subset of lung cancer cases that bear EGFR mutations. Several studies have reported the prerequisite role of and alterations in transdifferentiation. However, the mechanism underlying transdifferentiation remains understudied, and definitive additional events, the third hit, for transdifferentiation have not yet been identified. In addition, no prospective experiments provide direct evidence for transdifferentiation. In this study, we show that FGF9 upregulation plays an essential role in transdifferentiation. An integrative omics analysis of paired tumor samples from a patient with transdifferentiated SCLC exhibited robust upregulation of FGF9. Furthermore, FGF9 upregulation was confirmed at the protein level in four of six (66.7%) paired samples. FGF9 induction transformed mouse lung adenocarcinoma-derived cells to SCLC-like tumors through cell autonomous activation of the FGFR pathway. treatment of transdifferentiated SCLC-like tumors with the pan-FGFR inhibitor AZD4547 inhibited growth. In addition, FGF9 induced neuroendocrine differentiation, a pathologic characteristic of SCLC, in established human lung adenocarcinoma cells. Thus, the findings provide direct evidence for FGF9-mediated SCLC transdifferentiation and propose the FGF9-FGFR axis as a therapeutic target for transdifferentiated SCLC. SIGNIFICANCE: This study demonstrates that FGF9 plays a role in the transdifferentiation of lung adenocarcinoma to small cell lung cancer.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-4048DOI Listing
July 2021

Myeloid lncRNA LOUP Mediates Opposing Regulatory Effects of RUNX1 and RUNX1-ETO in t(8;21) AML.

Blood 2021 05 10. Epub 2021 May 10.

Harvard Medical School Initiative for RNA Medicine, Harvard Medical School, Boston, Massachusetts, United States.

The mechanism underlying cell type-specific gene induction conferred by ubiquitous transcription factors as well as disruptions caused by their chimeric derivatives in leukemia is not well understood. Here we investigate whether RNAs coordinate with transcription factors to drive myeloid gene transcription. In an integrated genome-wide approach surveying for gene loci exhibiting concurrent RNA- and DNA-interactions with the broadly expressed transcription factor RUNX1, we identified the long noncoding RNA LOUP. This myeloid-specific and polyadenylated lncRNA induces myeloid differentiation and inhibits cell growth, acting as a transcriptional inducer of the myeloid master regulator PU.1. Mechanistically, LOUP recruits RUNX1 to both the PU.1 enhancer and the promoter, leading to the formation of an active chromatin loop. In t(8;21) acute myeloid leukemia, wherein RUNX1 is fused to ETO, the resulting oncogenic fusion protein RUNX1-ETO limits chromatin accessibility at the LOUP locus, causing inhibition of LOUP and PU.1 expression. These findings highlight the important role of the interplay between cell type-specific RNAs and transcription factors as well as their oncogenic derivatives in modulating lineage-gene activation and raise the possibility that RNA regulators of transcription factors represent alternative targets for therapeutic development.
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http://dx.doi.org/10.1182/blood.2020007920DOI Listing
May 2021

Preclinical characterization of mobocertinib highlights the putative therapeutic window of this novel EGFR inhibitor to EGFR exon 20 insertion mutations.

JTO Clin Res Rep 2021 Mar 6;2(3). Epub 2020 Oct 6.

Department of Medicine, Division of Hematology/Oncology, Harvard Medical School, Boston, MA, United States of America.

Background: Epidermal growth factor receptor (EGFR) exon 20 insertion mutations account for 10% of all EGFR mutations and are mostly insensitive to approved EGFR-tyrosine kinase inhibitors (EGFR-TKIs). Novel EGFR-TKIs have been developed or repurposed for these mutants. A limited number of preclinical studies have detailed these EGFR-TKIs. We sought to use commercially available mobocertinib (TAK-788) to characterize the preclinical therapeutic window of this EGFR-TKI against EGFR mutations and to probe possible on-target mechanisms of resistance (EGFR-C797S).

Methods: We used models of EGFR mutations to probe representative 1, 2, 3 generation, and in-development EGFR exon 20-active (poziotinib, mobocertinib) TKIs. We also introduced EGFR-C797S to these models to identify mechanisms of resistance.

Results: Cells driven by the most common EGFR exon 20 insertion mutations (A767_V769dupASV, D770_N771 insSVD, H773_V774insH and others) were inhibited by in-development EGFR TKIs at doses below those affecting EGFR-wildtype; albeit more common EGFR mutations (exon 19 deletions and L858R) were inhibited more readily by mobocertinib and poziotinib. Mobocertinib was able to inhibit phosphorylation of EGFR in multiple preclinical models. The presence of EGFR-C797S led to >200-fold resistance in proliferation assays probing mobocertinib and osimertinib. Review of clinical studies of mobocertinib disclosed responses that could be lasting.

Conclusions: This is one of the initial reports to characterize the novel EGFR TKI mobocertinib and highlights its broad activity against EGFR mutants plus the therapeutic window to EGFR exon 20 insertion mutations; as well as EGFR-C797S as a possible mechanism of resistance. Further clinical development of mobocertinib merits continuation.
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http://dx.doi.org/10.1016/j.jtocrr.2020.100105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7959160PMC
March 2021

HSP90 inhibition overcomes EGFR amplification-induced resistance to third-generation EGFR-TKIs.

Thorac Cancer 2021 03 20;12(5):631-642. Epub 2021 Jan 20.

Division of Cancer Immunology, Exploratory Oncology Research & Clinical Trial Center (EPOC), National Cancer Center, Chiba, Japan.

Background: Patients with non-small cell lung cancer (NSCLC) harboring activating EGFR mutations are sensitive to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) but inevitably develop resistance to the inhibitors mostly through acquisition of the secondary T790M mutation. Although third-generation EGFR-TKIs overcome this resistance by selectively inhibiting EGFR with EGFR-TKI-sensitizing and T790M mutations, acquired resistance to third-generation EGFR-TKIs invariably develops.

Methods: Next-generation sequencing (NGS) and fluorescence in situ hybridization (FISH) analysis were performed in an EGFR T790M-mutated NSCLC patient who had progressed after a third-generation EGFR-TKI, TAS-121. EGFR-mutated cell lines were subjected to a cell proliferation assay and western blotting analysis with EGFR-TKIs and a heat shock protein 90 (HSP90) inhibitor.

Results: NGS and FISH analysis revealed EGFR amplification in the resistant cancer cells. While EGFR L858R/T90M-mutated cell line was sensitive to osimertinib or TAS-121 in vitro, EGFR-overexpressing cell lines displayed resistance to these EGFR-TKIs. Western blot analysis showed that EGFR phosphorylation and overexpression of EGFR in cell lines was not suppressed by third-generation EGFR-TKIs. In contrast, an HSP90 inhibitor reduced total and phosphorylated EGFR and inhibited the proliferation of resistant cell lines.

Conclusions: EGFR amplification confers resistance to third-generation EGFR-TKIs which can be overcome by HSP90 inhibition. The results provide a preclinical rationale for the use of HSP90 inhibitors to overcome EGFR amplification-mediated resistance.
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http://dx.doi.org/10.1111/1759-7714.13839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919131PMC
March 2021

Combination treatment with a PI3K/Akt/mTOR pathway inhibitor overcomes resistance to anti-HER2 therapy in PIK3CA-mutant HER2-positive breast cancer cells.

Sci Rep 2020 12 10;10(1):21762. Epub 2020 Dec 10.

Department of Breast and Medical Oncology, National Cancer Center Hospital East, Kashiwa, Japan.

Amplification and/or overexpression of human epidermal growth factor receptor 2 (HER2) are observed in 15-20% of breast cancers (HER2+ breast cancers), and anti-HER2 therapies have significantly improved prognosis of patients with HER2+ breast cancer. One resistance mechanism to anti-HER2 therapies is constitutive activation of the phosphoinositide 3-kinase (PI3K) pathway. Combination therapy with small-molecule inhibitors of AKT and HER2 was conducted in HER2+ breast cancer cell lines with or without PIK3CA mutations, which lead to constitutive activation of the PI3K pathway. PIK3CA mutations played important roles in resistance to single-agent anti-HER2 therapy in breast cancer cell lines. Combination therapy of a HER2 inhibitor and an AKT inhibitor, as well as other PI3K pathway inhibitors, could overcome the therapeutic limitations associated with single-agent anti-HER2 treatment in PIK3CA-mutant HER2+ breast cancer cell lines. Furthermore, expression of phosphorylated 4E-binding protein 1 (p4EBP1) following the treatment correlated with the antiproliferative activities of the combination, suggesting that p4EBP1 may have potential as a prognostic and/or efficacy-linking biomarkers for these combination therapies in patients with HER2+ breast cancer. These findings highlight potential clinical strategies using combination therapy to overcome the limitations associated with single-agent anti-HER2 therapies in patients with HER2+ breast cancer.
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http://dx.doi.org/10.1038/s41598-020-78646-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7729878PMC
December 2020

Acquired Resistance to Osimertinib Plus Savolitinib Is Mediated by -D1228 and -Y1230 Mutations in -Mutated -Amplified Lung Cancer.

JTO Clin Res Rep 2020 Nov 20;1(4):100071. Epub 2020 Jun 20.

Department of Medicine, Division of Medical Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.

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http://dx.doi.org/10.1016/j.jtocrr.2020.100071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305494PMC
November 2020

Clinical Benefit of Tyrosine Kinase Inhibitors in Advanced Lung Cancer with EGFR-G719A and Other Uncommon EGFR Mutations.

Oncologist 2021 04 6;26(4):281-287. Epub 2020 Oct 6.

Division of Medical Oncology, Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.

The optimal management of advanced non-small cell lung cancer (NSCLC) with noncanonical epidermal growth factor receptor (EGFR) mutations (i.e., exon 19 deletion and exon 21 L858R) is constrained by the heterogeneous behavior of individual uncommon mutations and limited prospective clinical data in this setting. Despite encouraging results with osimertinib from a recently published phase II trial from South Korea, afatinib remains the only currently approved drug for patients with tumors harboring uncommon EGFR mutations (i.e., S768I, L861Q, and/or G719X). When used at the standard dose of 40 mg daily, afatinib is associated with significant rates of treatment-related adverse events, leading to frequent dose reductions and treatment discontinuations. We report a case of a woman with advanced NSCLC harboring EGFR-G719A mutation treated with afatinib (at an off-label pulse dose strategy that merits further evaluation in prospective studies) with sustained partial response for 20 months with manageable expected toxicities. Subsequent disease progression was mediated by off-target pan-EGFR inhibitor (including osimertinib)-resistant KRAS mutation and not by acquisition of EGFR-T790M. We further present the current state of evidence in the literature behind use of first-, second-, and third-generation tyrosine kinase inhibitors and summarize the evolving spectrum of activity ascribed to osimertinib (and newer EGFR inhibitors with a more favorable therapeutic window and intracranial penetration) in this population of patients with advanced NSCLC and uncommon EGFR mutations. KEY POINTS: Uncommon EGFR mutations characterize a heterogeneous group of patients with advanced non-small cell lung cancer (NSCLC). Afatinib is the only currently U.S. Food and Drug Administration-approved drug for management of advanced NSCLC with uncommon EGFR mutations (S768I, L861Q, and/or G719X). Afatinib treatment at 40 mg daily is associated with high rates of adverse events and dose reductions; alternative strategies including pulse intermittent dosing should be evaluated prospectively. Osimertinib (with favorable safety profile and intracranial penetration) has shown promising results in this population in a phase II trial from South Korea; additional trials are ongoing.
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http://dx.doi.org/10.1002/onco.13537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018319PMC
April 2021

Long-read sequencing for non-small-cell lung cancer genomes.

Genome Res 2020 09 4;30(9):1243-1257. Epub 2020 Sep 4.

Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba 277-8562, Japan.

Here, we report the application of a long-read sequencer, PromethION, for analyzing human cancer genomes. We first conducted whole-genome sequencing on lung cancer cell lines. We found that it is possible to genotype known cancerous mutations, such as point mutations. We also found that long-read sequencing is particularly useful for precisely identifying and characterizing structural aberrations, such as large deletions, gene fusions, and other chromosomal rearrangements. In addition, we identified several medium-sized structural aberrations consisting of complex combinations of local duplications, inversions, and microdeletions. These complex mutations occurred even in key cancer-related genes, such as , , , and The biological relevance of those mutations was further revealed by epigenome, transcriptome, and protein analyses of the affected signaling pathways. Such structural aberrations were also found in clinical lung adenocarcinoma specimens. Those structural aberrations were unlikely to be reliably detected by conventional short-read sequencing. Therefore, long-read sequencing may contribute to understanding the molecular etiology of patients for whom causative cancerous mutations remain unknown and therapeutic strategies are elusive.
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http://dx.doi.org/10.1101/gr.261941.120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545141PMC
September 2020

Alternative splicing of APOBEC3D generates functional diversity and its role as a DNA mutator.

Int J Hematol 2020 Sep 12;112(3):395-408. Epub 2020 Jun 12.

Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, E/CLS-407, 330 Brookline Avenue, Boston, MA, 02215, USA.

The apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC) protein family members have cytidine deaminase activity and can induce cytosine to uracil transition in nucleic acid. The main function of APOBEC3 (A3) proteins is to trigger an innate immune response to viral infections. Recent reports have shown that several APOBEC family proteins such as A3B can induce somatic mutations into genomic DNA and thus promote cancer development. However, the role of A3D on somatic mutations is unclear. Here, we identified the alternative splicing of A3D, and investigated each splice variant's subcellular localization and role in DNA mutagenesis. We identified four A3D variants, which all have one or two cytidine deaminase domains. The full-length form of A3D (variant 1) and truncated forms of A3D (variant 2, 6, 7) showed the ability to induce C/G to T/A transitions in foreign DNA and genomic DNA and retained antiretroviral activity. Furthermore, we demonstrated that A3D and A3B could induce deletions that are possibly repaired by microhomology-mediated end joining (MMEJ). Taken together, our experiments illustrated that alternative splicing generates functional diversity of A3D, and some variants can act as DNA mutators in genomic DNA.
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http://dx.doi.org/10.1007/s12185-020-02904-yDOI Listing
September 2020

Effects of gefitinib treatment on cellular uptake of extracellular vesicles in EGFR-mutant non-small cell lung cancer cells.

Int J Pharm 2019 Dec 11;572:118762. Epub 2019 Oct 11.

NanoSquare Research Institute, Research Center for the 21st Century, Organization for Research Promotion, Osaka Prefecture University, Sakai, Osaka 599-8570, Japan; Graduate School of Science, Osaka Prefecture University, Sakai, Osaka 599-8570, Japan. Electronic address:

Extracellular vesicles (exosomes, EVs) are cell membrane particles (30-200 nm) secreted by virtually all cells. During intercellular communication in the body, secreted EVs play crucial roles by carrying functional biomolecules (e.g., microRNAs and enzymes) into other cells to affect cellular function, including disease progression. We previously reported that the macropinocytosis pathway contributes greatly to the efficient cellular uptake of EVs. The activation of growth factor receptors, such as epidermal growth factor receptor (EGFR), induces macropinocytosis. In this study, we demonstrated the effects of gefitinib, a tyrosine kinase inhibitor of EGFR, on the cellular uptake of EVs. In EGFR-mutant HCC827 non-small cell lung cancer (NSCLC) cells, which are sensitive to gefitinib, macropinocytosis was suppressed by gefitinib treatment. However, the cellular uptake of EVs was increased by gefitinib treatment, whereas that of liposomes was reduced. In accordance with the results of the cellular uptake studies, the anti-cancer activity of doxorubicin (DOX)-loaded EVs in HCC827 cells was significantly increased in the presence of gefitinib, whereas the activity of DOX-loaded liposomes was reduced. The digestion of EV proteins by trypsin did not affect uptake, suggesting that the cellular uptake of EVs might not be mediated by EV proteins. These results suggest that gefitinib can enhance cell-to-cell communication via EVs within the tumor microenvironment. In addition, EVs show potential as drug delivery vehicles in combination with gefitinib for the treatment of patients harboring EGFR-mutant NSCLC tumors.
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http://dx.doi.org/10.1016/j.ijpharm.2019.118762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6899172PMC
December 2019

TAS6417/CLN-081 Is a Pan-Mutation-Selective EGFR Tyrosine Kinase Inhibitor with a Broad Spectrum of Preclinical Activity against Clinically Relevant Mutations.

Mol Cancer Res 2019 11 29;17(11):2233-2243. Epub 2019 Aug 29.

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

Despite the worldwide approval of three generations of EGFR tyrosine kinase inhibitors (TKI) for advanced non-small cell lung cancers with mutations, no TKI with a broad spectrum of activity against all clinically relevant mutations is currently available. In this study, we sought to evaluate a covalent mutation-specific EGFR TKI, TAS6417 (also named CLN-081), with the broadest level of activity against mutations with a prevalence of ≥1%. Lung cancer and genetically engineered cell lines, as well as murine xenograft models were used to evaluate the efficacy of TAS6417 and other approved/in-development EGFR TKIs (erlotinib, afatinib, osimertinib, and poziotinib). We demonstrate that TAS6417 is a robust inhibitor against the most common mutations (exon 19 deletions and L858R) and the most potent against cells harboring -T790M (first/second-generation TKI resistance mutation). In addition, TAS6417 has activity in cells driven by less common -G719X, L861Q, and S768I mutations. For recalcitrant exon 20 insertion mutations, selectivity indexes (wild-type EGFR/mutant EGFR ratio of inhibition) favored TAS6417 in comparison with poziotinib and osimertinib, indicating a wider therapeutic window. Taken together, we demonstrate that TAS6417 is a potent EGFR TKI with a broad spectrum of activity and a wider therapeutic window than most approved/in-development generations of EGFR inhibitors. IMPLICATIONS: TAS6417/CLN-081 is a potent EGFR TKI with a wide therapeutic window and may be effective in lung cancer patients with clinically relevant mutations.
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http://dx.doi.org/10.1158/1541-7786.MCR-19-0419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6872223PMC
November 2019

EGFR-Mutated Lung Cancers Resistant to Osimertinib through EGFR C797S Respond to First-Generation Reversible EGFR Inhibitors but Eventually Acquire EGFR T790M/C797S in Preclinical Models and Clinical Samples.

J Thorac Oncol 2019 11 1;14(11):1995-2002. Epub 2019 Aug 1.

Department of Medicine, Division of Medical Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts. Electronic address:

Introduction: Osimertinib is approved for advanced EGFR-mutated NSCLC, and identification of on-target mechanisms of resistance (i.e., EGFR C797S) to this third-generation EGFR inhibitor are evolving. Whether durable control of subsequently osimertinib-resistant NSCLC with the EGFR-sensitizing mutation (SM)/C797S is possible with first-generation EGFR inhibitors (such as gefitinib or erlotinib) remains underreported, as does the resultant acquired resistance profile.

Methods: We used N-ethyl-N-nitrosourea mutagenesis to determine the profile of EGFR SM/C797S preclinical models exposed to reversible EGFR inhibitors. In addition, we retrospectively probed a case of EGFR SM lung adenocarcinoma treated with first-line osimertinib, followed by second-line erlotinib in the setting of EGFR SM/C797S.

Results: Use of N-ethyl-N-nitrosourea mutagenesis against the background of EGFR L858R/C797S in conjunction with administration of gefitinib revealed preferential outgrowth of cells with EGFR L858R/T790M/C797S. A patient with EGFR delE746_T751insV NSCLC was treated with osimertinib with sustained response for 10 months before acquiring EGFR C797S. The patient was subsequently treated with erlotinib, with response for a period of 4 months, but disease progression ensued. Liquid biopsy disclosed EGFR delE746_T751insV with T790M and C797S present in cis.

Conclusion: EGFR SM NSCLC can acquire resistance to osimertinib through development of the EGFR C797S mutation. In this clinical scenario, the tumor may respond transiently to reversible first-generation EGFR inhibitors (gefitinib or erlotinib), but evolving mechanisms of on-target resistance-in clinical specimens and preclinical systems-indicate that EGFR C797S along with EGFR T790M can evolve. This report adds to the growing understanding of tumor evolution or adaptability to sequential EGFR inhibition and augments support for exploring combination therapies to delay or prevent on-target resistance.
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http://dx.doi.org/10.1016/j.jtho.2019.07.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823139PMC
November 2019

Styryl quinazolinones and its ethynyl derivatives induce myeloid differentiation.

Bioorg Med Chem Lett 2019 08 20;29(16):2286-2289. Epub 2019 Jun 20.

Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA; Division of Translational Genomics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba 277-8577, Japan. Electronic address:

The tumor suppressor transcription factor CCAAT enhancer-binding protein α (C/EBPα) expression is downregulated in myeloid leukemias and enhancement of C/EBPα expression induces granulocytic differentiation in leukemic cells. Previously we reported that Styryl quinazolinones induce myeloid differentiation in HL-60 cells by upregulating C/EBPα expression. To identify more potent molecule that can induce leukemic cell differentiation we synthesized and evaluated new series of styryl quinazolinones, ethynyl styryl quinazolinones, styryl quinolinones and thienopyrimidinones. Thienopyrimidinones were found toxic and styryl quinolinones were found inactive. Ethynyl styryl quinazolinone 39 and styryl quinazolinone 5 were found active on par with the earlier reported analogues 1 and 2 suggesting that the 5-nitro furan-2-yl styryl quinazolinones find a real promise in leukemic cell differentiation. The improved potency of 5 suggested that further modifications in the 5-nitro furan-2-yl styryl quinazolinones can be at the phenyl substitution at the 3-position of the quinazolinone ring apart from the 5-position of the heteroaryl ring.
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http://dx.doi.org/10.1016/j.bmcl.2019.06.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8236261PMC
August 2019

Molecular dynamics simulation-guided drug sensitivity prediction for lung cancer with rare mutations.

Proc Natl Acad Sci U S A 2019 05 1;116(20):10025-10030. Epub 2019 May 1.

Division of Pulmonary Medicine, Department of Medicine, Keio University, School of Medicine, Shinjuku-ku, 160-8582 Tokyo, Japan.

Next generation sequencing (NGS)-based tumor profiling identified an overwhelming number of uncharacterized somatic mutations, also known as variants of unknown significance (VUS). The therapeutic significance of mutations outside mutational hotspots, consisting of >50 types, in nonsmall cell lung carcinoma (NSCLC) is largely unknown. In fact, our pan-nation screening of NSCLC without hotspot mutations ( = 3,779) revealed that the majority (>90%) of cases with rare mutations, accounting for 5.5% of the cohort subjects, did not receive EGFR-tyrosine kinase inhibitors (TKIs) as a first-line treatment. To tackle this problem, we applied a molecular dynamics simulation-based model to predict the sensitivity of rare EGFR mutants to EGFR-TKIs. The model successfully predicted the diverse in vitro and in vivo sensitivities of exon 20 insertion mutants, including a singleton, to osimertinib, a third-generation EGFR-TKI ( = 0.72, = 0.0037). Additionally, our model showed a higher consistency with experimentally obtained sensitivity data than other prediction approaches, indicating its robustness in analyzing complex cancer mutations. Thus, the in silico prediction model will be a powerful tool in precision medicine for NSCLC patients carrying rare mutations in the clinical setting. Here, we propose an insight to overcome mutation diversity in lung cancer.
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http://dx.doi.org/10.1073/pnas.1819430116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6525482PMC
May 2019

EGFR Exon 20 Insertion Mutations Display Sensitivity to Hsp90 Inhibition in Preclinical Models and Lung Adenocarcinomas.

Clin Cancer Res 2018 12 28;24(24):6548-6555. Epub 2018 Aug 28.

Department of Medicine, Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.

Purpose: exon 20 insertions account for up to 10% of all mutations in lung adenocarcinomas, representing the third most common cluster of mutations. The management of advanced cancers with these mutations remains elusive, without an approved inhibitor.

Experimental Design: Preclinical models of a representative set of EGFR exon 20 insertion mutations to evaluate the efficacy of different inhibitors and description of the clinical outcome of an advanced lung cancer.

Results: We show that select first-, second-, and third-generation EGFR inhibitors are unable to deter common EGFR exon 20 insertion mutants in concentrations that spare the wild-type kinase. Nonetheless, EGFR exon 20 insertion mutants associate with the Hsp90 chaperone system. We exploit this vulnerability to show that the nongeldanamycin Hsp90 inhibitor luminespib (formerly AUY922) degrades EGFR exon 20 mutations, downstream targets, and induces apoptosis. In addition, a patient whose EGFR inhibitor-insensitive lung adenocarcinoma harbored an exon 20 insertion mutation had a confirmed radiographic response to luminespib.

Conclusions: The report confirms that EGFR exon 20 mutations are dependent on Hsp90 and are readily inhibited by the Hsp90 inhibitor luminespib; a treatment strategy that has been pursued in a confirmatory clinical trial (NCT01854034) for this group of lung adenocarcinomas that currently represent an unmet clinical need in precision oncology.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-1541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6295229PMC
December 2018

Styryl Quinazolinones as Potential Inducers of Myeloid Differentiation via Upregulation of C/EBPα.

Molecules 2018 Aug 3;23(8). Epub 2018 Aug 3.

Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.

The CCAAT enhancer-binding protein α (C/EBPα) plays an important role in myeloid cell differentiation and in the enhancement of C/EBPα expression/activity, which can lead to granulocytic differentiation in acute myeloid leukemia (AML) cells. We found that styryl quinazolinones induce upregulation of C/EBPα expression, and thereby induce myeloid differentiation in human myeloid leukemia cell lines. We screened a series of active styryl quinazolinones and evaluated the structure⁻activity relationship (SAR) of these small molecules in inducing C/EBPα expression-thereby prompting the leukemic cells to differentiate. We observed that compound causes differentiation at 3 μM concentration, while induces differentiation at 10 μM concentration. We also observed an increase in the expression of neutrophil differentiation marker CD11b upon treatment with . Both the C/EBPα and C/EBPε levels were found to be upregulated by treatment with . These SAR findings are inspiration to develop further modified styryl quinazolinones, in the path of this novel differentiation therapy, which can contribute to the care of patients with AML.
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http://dx.doi.org/10.3390/molecules23081938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6222906PMC
August 2018

[Transcription factor-based therapies for acute myeloid leukemia].

Rinsho Ketsueki 2018;59(7):922-931

Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School.

Transcription factors are proteins that bind specific DNA-regulatory sequences and regulate gene transcription. In a hematopoietic system, transcription factors, such as C/EBPα, PU.1, and RUNX1, regulate the expression of essential genes to maintain the homeostasis in the bone marrow. The dysfunction of transcription factors mediated by gene mutations, chromosomal aberration, or aberrant expression can lead to cancer, including acute myeloid leukemia. Previously, transcription factors were not considered as therapeutic targets; however, a better understanding of cancer pathology and mechanisms underlying transcriptional regulation has enabled us to develop therapeutic agents that target transcription factors. C/EBPα is one of the essential transcription factors responsible for granulocytic differentiation and maturation. CEBPA mutation and/or low C/EBPα expression contribute to the pathogenesis of acute myeloid leukemia. Several therapeutic agents have been developed to increase C/EBPα activity, including ICCB280, which is a small molecule we identified by high-throughput screening. We believe that the novel therapeutic approach of targeting transcription factors will benefit patients with acute myeloid leukemia in the near future.
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http://dx.doi.org/10.11406/rinketsu.59.922DOI Listing
July 2019

Activity of Brigatinib in the Setting of Alectinib Resistance Mediated by ALK I1171S in ALK-Rearranged Lung Cancer.

J Thorac Oncol 2019 01 5;14(1):e1-e3. Epub 2018 Jul 5.

Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts. Electronic address:

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http://dx.doi.org/10.1016/j.jtho.2018.06.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6322846PMC
January 2019

Targeting transcription factors in acute myeloid leukemia.

Int J Hematol 2019 Jan 28;109(1):28-34. Epub 2018 Jun 28.

Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, USA.

Transcription factors recognize and bind to consensus sequence elements that are specific for each transcription factor, and the transcription factors then regulate downstream gene expression. In the bone marrow, transcription factors, such as C/EBPα, PU.1, and RUNX1, control essential genes to maintain the normal hematopoietic system. Dysregulation of transcription factors caused by gene mutations, chromosomal aberrations, or aberrant expression can lead to cancer, including acute myeloid leukemia. In the past, transcription factors were not considered "druggable" targets. However, a better understanding of the pathology of malignant tumors and mechanisms of transcriptional regulation has enabled us to develop novel therapeutic strategies that target transcription factors. In this review, we focus on transcription factors that play important roles in leukemogenesis and current efforts and prospects in the development of transcriptional therapy. We believe that such a therapeutic approach will benefit patients with cancers that involve acute myeloid leukemia in the near future.
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http://dx.doi.org/10.1007/s12185-018-2488-1DOI Listing
January 2019

Tumor biomarker testing in non-small-cell lung cancer: A decade of change.

Lung Cancer 2018 02 4;116:90-95. Epub 2018 Jan 4.

Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States. Electronic address:

Introduction: Although a growing list of essential genomic/immune-based biomarkers are linked to approved non-small-cell lung cancer (NSCLC) therapies worldwide, few reports have detailed the evolution of NSCLC predictive biomarker assessment in routine clinical practice.

Methods: We retrospectively reviewed the first one thousand plus NSCLC patient specimens from our institution analyzed for predictive biomarkers from 2004 to 2017 and evaluated patterns of testing as well as correlation with clinical-pathologic characteristics.

Results: The majority of 1009 NSCLC patients had advanced stages of adenocarcinoma with most tissues obtained from the lung, mediastinal/hilar nodes, or pleura. The majority of testing was performed on cytology or small biopsy specimens. All were tested for EGFR mutations, 895 for ALK rearrangement, 841 for KRAS mutation, 537 for ROS1 rearrangement, and 179 using comprehensive genomic profiling. Implementation of near-universal genomic biomarker testing at our institution for EGFR, ALK, ROS1 and PD-L1 all occurred within the first year following evidence of clinical activity or regulatory body approval of an associated inhibitor. The overall testing failure rate after use of the best specimen for the most common tests was ≤5.5%. A quarter of tumors had a driver oncogene identified (EGFR/ALK/ROS1/BRAF V600E) with an approved oral targeted therapy, with the highest prevalence in those patients with no or light (≤15 pack-years) history of tobacco use.

Conclusions: Tumor biomarker testing using clinical NSCLC specimens in routine oncologic care evolves rapidly following approval of targeted therapies linked to diagnostic assays. Our practice's decade plus experience highlights the rapid evolution of biomarker testing and confirms the therapeutic relevance of such testing in all patients-particularly those patients with light/no history of tobacco use.
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http://dx.doi.org/10.1016/j.lungcan.2018.01.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5806129PMC
February 2018

ZNF143 protein is an important regulator of the myeloid transcription factor C/EBPα.

J Biol Chem 2017 11 12;292(46):18924-18936. Epub 2017 Sep 12.

From the Cancer Science Institute, National University of Singapore, 117599 Singapore,

The transcription factor C/EBPα is essential for myeloid differentiation and is frequently dysregulated in acute myeloid leukemia. Although studied extensively, the precise regulation of its gene by upstream factors has remained largely elusive. Here, we investigated its transcriptional activation during myeloid differentiation. We identified an evolutionarily conserved octameric sequence, CCCAGCAG, ∼100 bases upstream of the transcription start site, and demonstrated through mutational analysis that this sequence is crucial for C/EBPα expression. This sequence is present in the genes encoding C/EBPα in humans, rodents, chickens, and frogs and is also present in the promoters of other C/EBP family members. We identified that ZNF143, the human homolog of the transcriptional activator STAF, specifically binds to this 8-bp sequence to activate C/EBPα expression in myeloid cells through a mechanism that is distinct from that observed in liver cells and adipocytes. Altogether, our data suggest that ZNF143 plays an important role in the expression of C/EBPα in myeloid cells.
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http://dx.doi.org/10.1074/jbc.M117.811109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5704476PMC
November 2017

Gefitinib Enhances Mitochondrial Biological Functions in NSCLCs with Mutations at a High Cell Density.

Anticancer Res 2017 09;37(9):4779-4788

NanoSquare Research Institution, Research Center for the 21st Century, Organization for Research Promotion, Osaka Prefecture University, Sakai, Japan

Background/aim: Gefitinib is a tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR) and has been approved for the treatment of non-small cell lung cancers (NSCLCs) with EGFR mutations. Here we demonstrated that gefitinib induced a significantly enhanced biological activity of succinate-tetrazolium reductase (STR) in mitochondria and mitochondrial membrane potential in HCC827 cells (EGFR mutation NSCLCs, sensitive to gefitinib) at a high cell density.

Materials And Methods: We assessed the biological activity (STR, mitochondrial membrane potential, expression level of Bcl-2 family proteins) of gefitinib on NSCLCs at different cell densities.

Results: The 3D cell culture experiments showed the enhanced mitochondrial biological activity in clustered cell culture treated with gefitinib. Interestingly, the expression levels of Bcl-x and Bax, were affected by the cellular number and gefitinib treatment. We also found that gefitinib prevented additive anticancer activity in the combinational treatment with doxorubicin, which induces mitochondria-dependent apoptotic cell death.

Conclusion: Our results indicate that gefitinib may work as a mitochondrial protector against combinational treatment with mitochondria-dependent anticancer agents in high-cell-density.
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http://dx.doi.org/10.21873/anticanres.11884DOI Listing
September 2017

Cases of ALK-Rearranged Lung Cancer with 5-Year Progression-Free Survival with Crizotinib as Initial Precision Therapy.

J Thorac Oncol 2017 11 10;12(11):e175-e177. Epub 2017 Jun 10.

Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts. Electronic address:

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http://dx.doi.org/10.1016/j.jtho.2017.06.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5659921PMC
November 2017

Prognostic significance of β-catenin expression in patients with non-small cell lung cancer: a meta-analysis.

Transl Lung Cancer Res 2017 Feb;6(1):97-108

Department of Respiratory Medicine, Jinling Hospital, Nanjing University School of Medicine, Nanjing 210002, China.

Background: β-catenin is a key component of the canonical Wnt pathway, which plays pivotal roles in malignant transformation and cancer progression. Several studies have reported the clinical significance of the expression level of β-catenin in different subcellular locations. This meta-analysis aimed to assess the prognostic value of β-catenin expression patterns in patients with non-small cell lung cancer (NSCLC).

Methods: PubMed and Embase databases were searched to identify all articles referring to the association between β-catenin expression level and outcomes of patients of NSCLC up to November 2016. We included eligible studies to summarize the extracted data in terms of pooled hazard ratios (HRs) and their 95% confidence intervals (95% CIs).

Results: A total of 24 studies published between 2000 and 2016 were eligible for this meta-analysis. The total number of patients with NSCLC included was 2,807. Pooled HRs and 95% CIs suggested that positive β-catenin expression in membrane was associated with higher survival rates (HR: 0.53; 95% CI: 0.32-0.87), whereas β-catenin expression in cytoplasm and nucleus had unfavorable impacts on survival rates with HR of 1.63 (95% CI: 1.34-1.99) and HR of 3.15 (95% CI: 1.97-5.05), respectively. But, there was no significant association between β-catenin expression in abnormal pattern with prognosis (HR: 1.38; 95% CI: 0.61-3.15). Publication bias was absent in all of the four outcomes. Sensitivity analysis revealed that the results of this meta-analysis were robust.

Conclusions: Reduced membranous β-catenin, positive expression of cytoplasmic or nuclear β-catenin is all correlated with poor prognosis, although we did not identify a significant association between abnormal β-catenin expression and clinical outcome of NSCLC patients. The meta-analysis suggested that membranous, cytoplasmic and nuclear β-catenin all could serve as an important prognosticator for patients with NSCLC.
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http://dx.doi.org/10.21037/tlcr.2017.02.07DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5344847PMC
February 2017

Mutations in TP53, PIK3CA, PTEN and other genes in EGFR mutated lung cancers: Correlation with clinical outcomes.

Lung Cancer 2017 04 25;106:17-21. Epub 2017 Jan 25.

Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States. Electronic address:

Introduction: The degree and duration of response to epidermal growth factor receptor (EGFR) inhibitors in EGFR mutated lung cancer are heterogeneous. We hypothesized that the concurrent genomic landscape of these tumors, which is currently unknown in view of the prevailing single gene assay diagnostic paradigm in clinical practice, could play a role in clinical outcomes and/or mechanisms of resistance.

Methods: We retrospectively probed our institutional lung cancer database for tumors with EGFR kinase domain mutations that were also evaluated by more comprehensive molecular profiling, and evaluated tumor response to EGFR tyrosine kinase inhibitors (TKIs).

Results: Out of 171 EGFR mutated tumor-patient cases, 20 were sequenced using at least a limited comprehensive genomic profiling platform. 50% harbored concurrent TP53 mutation, 10% PIK3CA mutation, 5% PTEN mutation, among others. The response rate to EGFR TKIs, the median progression-free survival (PFS) to TKIs, the percentage of EGFR-T790M TKI resistance and survival had higher trends in EGFR mutant/TP53 wild-type cases when compared to EGFR mutant/TP53 mutant tumors (all p >0.05 without statistical significance); with a significantly longer median PFS in EGFR-exon 19 deletion mutant/TP53 wild-type cancers treated with 1st generation EGFR TKIs (p=0.035).

Conclusions: Concurrent mutations, specifically TP53, are common in EGFR mutated lung cancer and may alter clinical outcomes. Additional cohorts will be needed to determine if comprehensive molecular profiling adds clinically relevant information to single gene assay identification in oncogene-driven lung cancers.
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http://dx.doi.org/10.1016/j.lungcan.2017.01.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5351777PMC
April 2017

Correlation between Classic Driver Oncogene Mutations in EGFR, ALK, or ROS1 and 22C3-PD-L1 ≥50% Expression in Lung Adenocarcinoma.

J Thorac Oncol 2017 05 16;12(5):878-883. Epub 2017 Jan 16.

Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts. Electronic address:

Introduction: Targeted somatic genomic analysis (EGFR, anaplastic lymphoma receptor tyrosine kinase gene [ALK], and ROS1) and programmed death ligand 1 (PD-L1) tumor proportion score (TPS) determined by immunohistochemistry (IHC) are used for selection of first-line therapies in advanced lung cancer; however, the frequency of overlap of these biomarkers in routine clinical practice is poorly reported.

Methods: We retrospectively probed the first 71 pairs of patients with lung adenocarcinoma from our institution. They were analyzed for PD-L1 by IHC using the clone 22C3 pharmDx kit (Agilent Technologies, Santa Clara, CA) and evaluated for co-occurrence of genomic aberrations and clinicopathologic characteristics.

Results: Surgical resection specimens, small biopsy (transbronchial or core needle) samples, and cytologic cell blocks (needle aspirates or pleural fluid) were tested. A PD-L1 TPS of at least ≥50% was seen in 29.6% of tumors. Of 19 tumors with EGFR mutations, ALK fluorescence in situ hybridization positivity, or ROS1 fluorescence in situ hybridization positivity, 18 had a PD-L1 TPS less than 50% versus only one tumor with a PD-L1 TPS of at least 50% (p = 0.0073). Tumors with a PD-L1 TPS of at least 50% were significantly associated with smoking status compared with tumors with a PD-L1 TPS less than 50% but were not associated with patient sex, ethnicity, tumor stage, biopsy site, or biopsy type/preparation.

Conclusions: PD-L1 IHC can be performed on routine clinical lung cancer specimens. A TPS of at least 50% seldom overlaps with presence of driver oncogenes with approved targeted therapies. Three biomarker-specified groups of advanced lung adenocarcinomas can now be defined, each paired with a specific palliative first-line systemic therapy of proven clinical benefit: (1) EGFR/ALK/ROS1-affected adenocarcinoma paired with a matched tyrosine kinase inhibitor (∼20% of cases), (2) PD-L1-enriched adenocarcinoma (TPS ≥50%) paired with anti-PD-1 pembrolizumab (∼30% of cases), and (3) biomarker-negative (i.e., EGFR/ALK/ROS1/PD-L1-negative) adenocarcinoma paired with platinum doublet chemotherapy with or without bevacizumab (∼50% of cases).
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http://dx.doi.org/10.1016/j.jtho.2016.12.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5403565PMC
May 2017

De novo ALK kinase domain mutations are uncommon in kinase inhibitor-naïve ALK rearranged lung cancers.

Lung Cancer 2016 09 14;99:17-22. Epub 2016 Jun 14.

Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. Electronic address:

Introduction: Anaplastic lymphoma kinase (ALK) rearranged lung adenocarcinomas are responsive to the multitargeted ALK inhibitor crizotinib. One of the common mechanisms of resistance to crizotinib is the acquisition of ALK kinase domain mutations. However, the presence of ALK mutations in crizotinib-naïve tumors has not been widely reported and it is unclear if de novo ALK mutations affect the response to crizotinib.

Methods: We analyzed preclinical models of ALK rearranged lung cancers that were sensitive/resistant to ALK inhibitors, probed our institutional and other lung cancer databases for tumors with ALK kinase domain mutations, and evaluated tumor response to crizotinib.

Results: ALK rearranged cell lines with ALK kinase domain mutations were heterogeneously less inhibited by increasing concentrations of crizotinib than cells driven solely by EML4-ALK fusions. Previous ALK rearranged lung cancer cohorts did not report ALK kinase mutations in inhibitor-naïve tumors. We identified one TKI-naïve ALK rearranged tumor with an ALK kinase domain mutation: ALK-S1206F (mutations at ALK-S1206 shifted crizotinib inhibitory curves only minimally in preclinical models). The never smoker whose tumor harbored de novo EML4-ALK-E5;A20+ALK-S1206F only achieved a 4-month radiographic response to crizotinib 250mg twice daily.

Conclusions: Combining data from our and prior cohorts, ALK kinase domain mutations were uncommon events (<3% of cases) in ALK inhibitor-naïve ALK rearranged lung adenocarcinomas but their effect on intrinsic resistance to ALK inhibitors should be better evaluated.
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http://dx.doi.org/10.1016/j.lungcan.2016.06.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5002311PMC
September 2016
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