Publications by authors named "Wei-Hsun Hsu"

14 Publications

  • Page 1 of 1

Lysine Deprivation Induces AKT-AADAT Signaling and Overcomes EGFR-TKIs Resistance in -Mutant Non-Small Cell Lung Cancer Cells.

Cancers (Basel) 2021 Jan 13;13(2). Epub 2021 Jan 13.

Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei 100, Taiwan.

Epidermal growth factor receptor () mutations are the most common driver genes in non-small cell lung cancer (NSCLC), especially in the Asian population. Although EGFR-tyrosine kinase inhibitors (TKIs) are influential in the treatment of -mutant NSCLC patients, acquired resistance inevitably occurs. Therefore, there is an urgent need to develop strategies to overcome this resistance. In addition, cancer cells with particular mutations appear more vulnerable to deficiency related to the availability of specific amino acids. However, it is still unknown which amino acid is affected in the case of -mutant NSCLC. In the present study, we established a screening platform based on amino acid deprivation and found that -mutant NSCLC cells are sensitive to short-term lysine deprivation. Moreover, we found that expression of the gene for the lysine catabolism enzyme α-aminoadipate aminotransferase () increased under lysine deprivation, revealing that can be regulated by EGFR-AKT signaling. Finally, we found that lysine reduction can not only enhance the cytostatic effect of single-agent osimertinib but also overcome the resistance of EGFR-TKIs in -mutant NSCLC cells. In summary, our findings suggest that the introduction of lysine stress might act as an advancement in -mutant NSCLC therapy and offer a strategy to overcome EGFR-TKI resistance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers13020272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828377PMC
January 2021

Association of Programmed Death-Ligand 1 Expression with Fusion Variants and Clinical Outcomes in Patients with Anaplastic Lymphoma Kinase-Positive Lung Adenocarcinoma Receiving Crizotinib.

Oncologist 2020 08 13;25(8):702-711. Epub 2020 May 13.

Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.

Background: Programmed death-ligand 1 (PD-L1) expression is associated with clinical outcomes of epidermal growth factor receptor (EGFR) mutant lung adenocarcinoma (ADC) treated with tyrosine kinase inhibitors (TKIs). However, whether PD-L1 expression plays a role in anaplastic lymphoma kinase (ALK)-positive lung ADC is unknown. We aimed to evaluate the impact of PD-L1 in patients with ALK-positive lung ADC receiving crizotinib.

Materials And Methods: PD-L1 expression was identified by immunohistochemistry (IHC). Reverse transcriptase-polymerase chain reaction was used for ALK variant detection, and immunofluorescence-based multiplex staining was applied for exploring immune cells in tumor microenvironments.

Results: A total of 78 patients with ALK-positive advanced ADC were enrolled in our study, of whom 52 received crizotinib. Compared with EGFR/ALK wild-type tumors, PD-L1 expression was lower in ALK-positive ADC. ALK fusion variants were identified in 32 patients, and those with variant 3 and 5 (short variants) had higher PD-L1 expression than those with other variants. The crizotinib objective response rate (ORR) and progression-free survival (PFS) was better in tumors with negative PD-L1 expression (ORR/PFS in PD-L1 0% vs. 1%-49% vs. 50%-100%: 60.7%/11.8 months vs. 38.5%/6.5 months vs. 36.4%/4.0 months, p = .007/.022). The multivariate Cox proportional hazards model revealed that PD-L1 0% (vs. ≥1%) was an independent factor for longer PFS (adjusted hazard ratio 0.322, 95% confidence interval 0.160-0.650, p = .002). Multiplex IHC in three cases showed a varied extent of immune cell infiltrations in tumors with different PD-L1 expression.

Conclusion: Positive PD-L1 expression was associated with unfavorable clinical outcomes in patients with ALK-positive lung ADC receiving crizotinib.

Implications For Practice: Not all lung adenocarcinoma with sensitizing driver mutations experienced durable responses to small-molecule tyrosine kinase inhibitors (TKIs). Similar to the negative impact of programmed death-ligand 1 (PD-L1) in epidermal growth factor receptor mutant tumors treated with TKIs, this study demonstrated that positive PD-L1 expression was also associated with worse response rate and shorter progression-free survival of anaplastic lymphoma kinase (ALK)-positive adenocarcinoma treated with crizotinib. Among different ALK fusion partners, tumors with short variants (V3 and V5) had higher PD-L1 compared with long variants (V1, V2, and V6). Testing PD-L1 before initiating crizotinib for ALK-positive lung cancer could be a simple method to provide important prognostic information.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1634/theoncologist.2020-0088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418350PMC
August 2020

Association between programmed death-ligand 1 expression, immune microenvironments, and clinical outcomes in epidermal growth factor receptor mutant lung adenocarcinoma patients treated with tyrosine kinase inhibitors.

Eur J Cancer 2020 01 21;124:110-122. Epub 2019 Nov 21.

Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei City, Taiwan.

Introduction: Besides being a predictive biomarker of response to immunotherapy in lung cancer in general, programmed death-ligand 1 (PD-L1) is not so well correlated with treatment outcomes of lung adenocarcinoma (ADC) harbouring epidermal growth factor receptor (EGFR) mutations, as reported studies are inconclusive and seldom addressed the issues of response to treatment and resistance. The primary objective is to evaluate the association of PD-L1 and EGFR tyrosine kinase inhibitor (TKI) efficacy, resistance, and relevant clinical outcomes. The secondary objective is to further explore the tumour microenvironments of EGFR mutant tumours with different PD-L1 expression.

Methods And Materials: Using immunohistochemical (IHC) staining, we retrospectively tested PD-L1 expression (Dako 22C3) in the pre-treatment tumours from advanced EGFR mutant lung ADC patients, of whom all were treated with TKIs. Multiplex IHC assay was applied for exploring immune cells in tumour microenvironments.

Results: A total of 153 Taiwanese patients were enrolled in our study, of whom a majority of cases were female (58.9%) and non-smokers (75.8%). The objective response rate (ORR) to EGFR TKI and progression-free survival (PFS) were better in patients with PD-L1 expression <50% (ORR/PFS in PD-L1 0% versus 1-49% versus ≥50%: 65.6%/12.5 months versus 56.4%/12.8 months versus 38.9%/5.9 months, P < 0.05). The multivariate analysis showed that PD-L1 <50% was an independent prognostic factor for longer PFS (hazard ratio (HR) 0.433, 95% confidence interval (CI) 0.250-0.751, P = 0.003). Furthermore, tumours with higher PD-L1 expression were less likely to develop a secondary T790M mutation (T790M+ in PD-L1 0% versus 1-49% versus ≥50%: 53.7% versus 35.7% versus 10%, P = 0.024). Multiplex IHC tests were applied in 15 cases and revealed a potential correlation between PD-L1, immune cells, and EGFR TKI responses.

Conclusions: Lower pre-treatment PD-L1 is associated with better ORR, PFS, and higher frequency of T790M resistance in EGFR TKI-treated lung ADC patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejca.2019.10.019DOI Listing
January 2020

Distinguishing human peripheral blood CD16 myeloid cells based on phenotypic characteristics.

J Leukoc Biol 2020 02 21;107(2):323-339. Epub 2019 Nov 21.

Dendritic Cell Research, ANZAC Research Institute, Sydney, New South Wales, Australia.

Myeloid lineage cells present in human peripheral blood include dendritic cells (DC) and monocytes. The DC are identified phenotypically as HLA-DR cells that lack major cell surface lineage markers for T cells (CD3), B cells (CD19, CD20), NK cells (CD56), red blood cells (CD235a), hematopoietic stem cells (CD34), and Mo that express CD14. Both DC and Mo can be phenotypically divided into subsets. DC are divided into plasmacytoid DC, which are CD11c , CD304 , CD85g , and myeloid DC that are CD11c . The CD11c DC are readily classified as CD1c DC and CD141 DC. Monocytes are broadly divided into the CD14 CD16 (classical) and CD14 CD16 subsets (nonclassical). A population of myeloid-derived cells that have DC characteristics, that is, HLA-DR and lacking lineage markers including CD14, but express CD16 are generally clustered with CD14 CD16 monocytes. We used high-dimensional clustering analyses of fluorescence and mass cytometry data, to delineate CD14 monocytes, CD14 CD16 monocytes (CD16 Mo), and CD14 CD16 DC (CD16 DC). We sought to identify the functional and kinetic relationship of CD16 DC to CD16 Mo. We demonstrate that differentiation of CD16 DC and CD16 Mo during activation with IFNγ in vitro and as a result of an allo-hematopoietic cell transplant (HCT) in vivo resulted in distinct populations. Recovery of blood CD16 DC in both auto- and allo-(HCT) patients after myeloablative conditioning showed similar reconstitution and activation kinetics to CD16 Mo. Finally, we show that expression of the cell surface markers CD300c, CCR5, and CLEC5a can distinguish the cell populations phenotypically paving the way for functional differentiation as new reagents become available.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/JLB.5A1119-362RRRDOI Listing
February 2020

CD83: Activation Marker for Antigen Presenting Cells and Its Therapeutic Potential.

Front Immunol 2019 7;10:1312. Epub 2019 Jun 7.

Dendritic Cell Research, ANZAC Research Institute, Sydney, NSW, Australia.

CD83 is a member of the immunoglobulin (Ig) superfamily and is expressed in membrane bound or soluble forms. Membrane CD83 (mCD83) can be detected on a variety of activated immune cells, although it is most highly and stably expressed by mature dendritic cells (DC). mCD83 regulates maturation, activation and homeostasis. Soluble CD83 (sCD83), which is elevated in the serum of patients with autoimmune disease and some hematological malignancies is reported to have an immune suppressive function. While CD83 is emerging as a promising immune modulator with therapeutic potential, some important aspects such as its ligand/s, intracellular signaling pathways and modulators of its expression are unclear. In this review we discuss the recent biological findings and the potential clinical value of CD83 based therapeutics in various conditions including autoimmune disease, graft-vs.-host disease, transplantation and hematological malignancies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2019.01312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6568190PMC
November 2020

The natural history of vascular and other complications in patients treated with nilotinib for chronic myeloid leukemia.

Blood Adv 2019 04;3(7):1084-1091

Department of Clinical Haematology, Austin Hospital, Melbourne, Australia.

Although second-generation tyrosine kinase inhibitors (TKIs) show superiority in achieving deep molecular responses in chronic myeloid leukemia in chronic phase (CML-CP) compared with imatinib, the differing adverse effect (AE) profiles need consideration when deciding the best drug for individual patients. Long-term data from randomized trials of nilotinib demonstrate an increased risk of vascular AEs (VAEs) compared with other TKIs, although the natural history of these events in response to dose modifications or cessation has not been fully characterized. We retrospectively reviewed the incidence of nilotinib-associated AEs in 220 patients with CML-CP at 17 Australian institutions. Overall, AEs of any grade were reported in 95 patients (43%) and prompted nilotinib cessation in 46 (21%). VAEs occurred in 26 patients (12%), with an incidence of 4.1 events per 100 patient-years. Multivariate analysis identified age ( = .022) and dyslipidemia ( = .007) as independent variables for their development. There was 1 fatal first VAE, whereas the remaining patients either continued nilotinib (14 patients) or stopped it immediately (11 patients). Recurrent VAEs were associated with ongoing therapy in 7 of 14 who continued (with 2 fatal VAEs) vs 1 of 11 who discontinued ( = .04). Nineteen of the 23 evaluable patients surviving a VAE ultimately stopped nilotinib, of whom 14 received an alternative TKI. Dose reduction or cessation because of VAEs did not adversely affect maintenance of major molecular response. These findings demonstrate that in contrast to other AEs, VAEs are ideally managed with nilotinib cessation because of the increased risk of additional events with its ongoing use.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2018028035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6457217PMC
April 2019

Checkpoint Kinase 1 Inhibition Enhances Cisplatin Cytotoxicity and Overcomes Cisplatin Resistance in SCLC by Promoting Mitotic Cell Death.

J Thorac Oncol 2019 06 14;14(6):1032-1045. Epub 2019 Feb 14.

Department of Oncology, Georgetown University Medical Center, Washington, DC. Electronic address:

Introduction: Platinum-based chemotherapy remains the standard treatment for patients with SCLC, but the benefit of the treatment is often hampered by rapid development of drug resistance. Thus far, there is no targeted therapy available for SCLC. More than 90% of SCLC tumors harbor mutations in the tumor suppressor gene tumor protein p53 (p53), an important DNA damage checkpoint regulator, and these tumor cells rely predominantly on the checkpoint kinases to control DNA damage response.

Methods: We examined whether and how inhibition of checkpoint kinase 1 (Chk1) affects cisplatin cytotoxicity in SCLC cells with and without p53 mutations, and evaluated the effect of Chk1 inhibitor and cisplatin combination in cisplatin-sensitive and -resistant preclinical models.

Results: Inhibition of Chk1 synergized with cisplatin to induce mitotic cell death in the p53-deficeint SCLC cells. The effect was regulated in part through activation of caspase 2 and downregulation of E2F transcription factor 1 (E2F1). Furthermore, Chk1 inhibitors prexasertib and AZD7762 enhanced cisplatin antitumor activity and overcame cisplatin resistance in SCLC preclinical models in vitro an in vivo. We also observed that higher expression of Chk1 was associated with poorer overall survival of patients with SCLC.

Conclusions: Our data account Chk1 as a potential therapeutic target in SCLC, and rationalize clinical development of Chk1 inhibitor and cisplatin combinational strategy for the treatment of SCLC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtho.2019.01.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6534433PMC
June 2019

Tumor PD-L1 Expression and Clinical Outcomes in Advanced-stage Non-Small Cell Lung Cancer Patients Treated with Nivolumab or Pembrolizumab: Real-World Data in Taiwan.

J Cancer 2018 19;9(10):1813-1820. Epub 2018 Apr 19.

Department of Internal Medicine, National Taiwan University Hospital, Taipei City, Taiwan.

Immunotherapy that targets programmed death protein-1 (PD-1) provides improved treatment efficacy and survival in patients with metastatic non-small cell lung cancer (NSCLC), especially those with high tumor expression of PD-L1. However, data on this treatment are mostly from clinical trials enrolling highly selected patients. The real-world experience of anti-PD-1 treatment and the usefulness of tumor PD-L1 expression in prediction of treatment response are largely unknown. We retrospectively reviewed patients with stage IIIB/ IV NSCLC who received monotherapy with nivolumab or pembrolizumab, and evaluated response using RECIST 1.1 criteria. Factors associated with treatment response, progression free survival (PFS), and overall survival (OS) were determined. Seventy-four NSCLC patients out of 116 examined patients were included, most of whom had adenocarcinoma (48/74, 64.9%) and received immunotherapy as a third-line or subsequent treatment (51/74, 68.9%). The median PFS and OS were 1.8 and 7.9 months, respectively. The objective response rate was 32%, but only 47 of 74 patients were evaluable. Through multivariate analysis, epidermal growth factor receptor (EGFR) mutation was independently associated with a poor treatment response. Good performance status (ECOG≤1) and smoking were independently associated with better PFS and OS. Data on tumor PD-L1 expression were available in 43 patients (58%); higher PD-L1 expression correlated with better treatment response and longer PFS. Severe treatment-related adverse events were uncommon. The efficacy and safety of anti-PD-1 medications for advanced NSCLC were comparable in real-world and clinical settings, except in those with poor ECOG scores. Prediction of treatment response from tumor PD-L1 expression seemed practical.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7150/jca.24985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5968770PMC
April 2018

The incidence and natural history of dasatinib complications in the treatment of chronic myeloid leukemia.

Blood Adv 2017 May 15;1(13):802-811. Epub 2017 May 15.

Austin Hospital, Melbourne, Australia.

Dasatinib has shown superiority over imatinib in achieving molecular responses (MRs) in chronic phase chronic myeloid leukemia but with a different toxicity profile, which may impact its overall benefit. Reported toxicities include pleural effusions and pulmonary hypertension, and although the incidence of these events is well described, response to therapy and impact of dose modifications on toxicity has not been comprehensively characterized in a real-world setting. We retrospectively reviewed the incidence of dasatinib adverse events in 212 chronic phase chronic myeloid leukemia patients at 17 Australian institutions. Adverse events were reported in 116 patients (55%), most commonly pleural effusions (53 patients, 25%), which was the predominant cause of permanent drug cessation. Age and dose were risk factors for pleural effusion ( < .01 and .047, respectively). Recurrence rates were higher in those who remained on 100 mg compared with those who dose reduced ( = .041); however, recurrence still occurred at 50 mg. Patients who developed pleural effusions were more likely to have achieved MR4.5 after 6 months of dasatinib than those without effusions ( = .008). Pulmonary hypertension occurred in 5% of patients, frequently in association with pleural effusion, and was reversible upon dasatinib cessation in 6 of 7 patients. Dose reductions and temporary cessations had minimal impact on MR rates. Our observations suggest that by using the lowest effective dose in older patients to minimize the effusion risk, dose modification for cytopenias, and care with concomitant antiplatelet therapy, the necessity for permanent dasatinib cessation due to toxicity is likely to be minimal in immunologically competent patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2016003889DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5727806PMC
May 2017

Inhibition of AKT1 signaling promotes invasion and metastasis of non-small cell lung cancer cells with K-RAS or EGFR mutations.

Sci Rep 2017 08 1;7(1):7066. Epub 2017 Aug 1.

Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.

Accumulating evidence supports a role of the PI3K-AKT pathway in the regulation of cell motility, invasion and metastasis. AKT activation is known to promote metastasis, however under certain circumstances, it also shows an inhibitory activity on metastatic processes, and the cause of such conflicting results is largely unclear. Here we found that AKT1 is an important regulator of metastasis and down-regulation of its activity is associated with increased metastatic potential of A549 cells. Inhibition of AKT1 enhanced migration and invasion in KRAS- or EGFR-mutant non-small cell lung cancer (NSCLC) cells. The allosteric AKT inhibitor MK-2206 promoted metastasis of KRAS-mutated A549 cells in vivo. We next identified that the phosphorylation of Myristoylated alanine-rich C-kinase substrate (MARCKS) and LAMC2 protein level were increased with AKT1 inhibition, and MARCKS or LAMC2 knockdown abrogated migration and invasion induced by AKT1 inhibition. This study unravels an anti-metastatic role of AKT1 in the NSCLC cells with KRAS or EGFR mutations, and establishes an AKT1-MARCKS-LAMC2 feedback loop in this regulation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-017-06128-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5539338PMC
August 2017

Bone Marrow Graft-Versus-Host Disease in Major Histocompatibility Complex-Matched Murine Reduced-Intensity Allogeneic Hemopoietic Cell Transplantation.

Transplantation 2017 11;101(11):2695-2704

1 Westmead Institute for Medical Research, New South Wales, Australia. 2 University of Sydney, Sydney, Australia. 3 Dendritic Cell Research, ANZAC Research Institute, Sydney, Australia. 4 Sydney Medical School, University of Sydney, Sydney, Australia.

Background: Most clinical allogeneic hemopoietic cell transplants (alloHCT) are now performed using reduced-intensity conditioning (RIC) instead of myeloablative conditioning (MAC); however, the biology underlying this treatment remains incompletely understood.

Methods: We investigated a murine model of major histocompatibility complex-matched multiple minor histocompatibility antigen-mismatched alloHCT using bone marrow (BM) cells and splenocytes from B6 (H-2) donor mice transplanted into BALB.B (H-2) recipients after RIC with fludarabine of 100 mg/kg per day for 5 days, cyclophosphamide of 60 mg/kg per day for 2 days, and total body irradiation (TBI).

Results: The lowest TBI dose capable of achieving complete donor chimerism in this mouse strain combination was 325 cGy given as a single fraction. Mice that underwent RIC had a reduced incidence and delayed onset of graft-versus-host disease (GVHD) and significantly prolonged survival compared with MAC-transplanted recipients (TBI of 850 cGy plus cyclophosphamide of 60 mg/kg per day for 2 days). Compared with syngeneic controls, RIC mice with GVHD showed evidence of BM suppression, have anemia, reduced BM cellularity, and showed profound reduction in BM B cell lymphopoiesis associated with damage to the endosteal BM niche. This was associated with an increase in BM CD8 effector T cells in RIC mice and elevated blood and BM plasma levels of T helper1 cytokines. Increasing doses of splenocytes resulted in increased incidence of GVHD in RIC mice.

Conclusions: We demonstrate that the BM is a major target organ of GVHD in an informative clinically relevant RIC mouse major histocompatibility complex-matched alloHCT model by a process that seems to be driven by CD8 effector T cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/TP.0000000000001733DOI Listing
November 2017

The Analysis of CD83 Expression on Human Immune Cells Identifies a Unique CD83+-Activated T Cell Population.

J Immunol 2016 12 11;197(12):4613-4625. Epub 2016 Nov 11.

ANZAC Research Institute, Concord Repatriation General Hospital, Sydney, New South Wales 2139, Australia;

CD83 is a member of the Ig gene superfamily, first identified in activated lymphocytes. Since then, CD83 has become an important marker for defining activated human dendritic cells (DC). Several potential CD83 mRNA isoforms have been described, including a soluble form detected in human serum, which may have an immunosuppressive function. To further understand the biology of CD83, we examined its expression in different human immune cell types before and after activation using a panel of mouse and human anti-human CD83 mAb. The mouse anti-human CD83 mAbs, HB15a and HB15e, and the human anti-human CD83 mAb, 3C12C, were selected to examine cytoplasmic and surface CD83 expression, based on their different binding characteristics. Glycosylation of CD83, the CD83 mRNA isoforms, and soluble CD83 released differed among blood DC, monocytes, and monocyte-derived DC, and other immune cell types. A small T cell population expressing surface CD83 was identified upon T cell stimulation and during allogeneic MLR. This subpopulation appeared specifically during viral Ag challenge. We did not observe human CD83 on unstimulated human natural regulatory T cells (Treg), in contrast to reports describing expression of CD83 on mouse Treg. CD83 expression was increased on CD4, CD8 T, and Treg cells in association with clinical acute graft-versus-host disease in allogeneic hematopoietic cell transplant recipients. The differential expression and function of CD83 on human immune cells reveal potential new roles for this molecule as a target of therapeutic manipulation in transplantation, inflammation, and autoimmune diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4049/jimmunol.1600339DOI Listing
December 2016

EMT is associated with, but does not drive resistance to ALK inhibitors among EML4-ALK non-small cell lung cancer.

Mol Oncol 2016 Apr 24;10(4):601-9. Epub 2015 Nov 24.

Department of Oncology, Georgetown University Medical Center, 3970 Reservoir Road NW, Washington, DC, 20007, USA. Electronic address:

ALK gene fusion occurs in approximately 3-7% of non-small cell lung cancer (NSCLC). For patients with ALK positive NCSLC, crizotinib and ceritinib are FDA approved ALK inhibitors, however, patients inevitably acquire resistance to such therapies typically within one to two years. Interrogation of in vitro ALK-positive NSCLC cell line models of acquired resistance to first and second-generation ALK inhibitors revealed acquired epithelial-to-mesenchymal transition (EMT) mechanisms. Here we demonstrated that knockdown of upregulated mesenchymal markers in acquired resistant lines decreased the invasive and migratory capabilities of the cells, however, it did not restore sensitivity to ALK inhibitors. Removing drug for 5 weeks from H3122 cell line that acquired resistance to ceritinib restored its sensitivity to ceritinib. In addition, HSP90 inhibitors ganetespib and 17-AAG were potent in inducing cell death in cell lines resistant to crizotinib and ceritinib. Taken together, EMT does not drive resistance to ALK inhibitors and HSP90 inhibition demonstrates more efficacy when further ALK inhibition may not. This study warrants more exploration of HSP90 inhibitors for ALK-positive patients who progress on 1st and 2nd line ALK inhibitor therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.molonc.2015.11.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5423150PMC
April 2016

Bcl-2-like protein 11 deletion polymorphism predicts survival in advanced non-small-cell lung cancer.

J Thorac Oncol 2014 Sep;9(9):1385-92

*Department of Oncology; †National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital; ‡Graduate Institute of Oncology and Cancer Research Center; §Graduate Institute of Clinical Medicine; ‖College of Medicine; ¶College of Life Science, National Taiwan University; #Institute of Statistical Science, Academia Sinica; **Department of Medical Imaging; and ††Department of Internal Medicine, National Taiwan University Hospital, Taiwan.

Introduction: Germline Bcl-2-like protein 11 (BIM) deletion polymorphism in Asian is a poor predictive factor for treatment outcomes to tyrosine kinase inhibitors (TKIs) in malignancies. We explored the impact of BIM deletion polymorphism on treatment outcome of advanced non-small-cell lung cancer (NSCLC).

Methods: We prospectively collected tissue samples, blood, and clinical data from two cohorts of advanced NSCLC patients. BIM deletion polymorphism was correlated with overall survival (OS) and progression-free survival (PFS) to epidermal growth factor receptor (EGFR) TKIs and chemotherapy treatment.

Results: BIM deletion polymorphism was detected in blood of 16.2% (33 of 204) patients. The PFS to first-line EGFR-TKIs in 153 patients were 8.6 and 4.6 months for patients with wild-type BIM and BIM deletion polymorphism, respectively (p = 0.004). Among 120 patients who received chemotherapies, the PFS to chemotherapies were 5.6 and 3.5 months for patients with wild-type BIM and BIM deletion polymorphism, respectively (p = 0.050). The OS of all 204 patients was 24.8 and 16.8 months for patients with wild-type BIM and BIM deletion polymorphism, respectively (p = 0.005). Multivariate analyses suggested that BIM deletion polymorphism was an independent predictor for shorter PFS to EGFR-TKIs (hazard ratio [HR] 2.15, p = 0.002), PFS to chemotherapy (HR 2.40, p = 0.016), and OS (HR 1.65, p = 0.039).

Conclusions: BIM deletion polymorphism predicts shorter PFS to EGFR-TKIs and OS in advanced NSCLC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/JTO.0000000000000238DOI Listing
September 2014