학술논문
BRAF V600E mutation and MET amplification as resistance pathways of the second-generation anaplastic lymphoma kinase (ALK) inhibitor alectinib in lung cancer.
Document Type
Academic Journal
Author
Shi R; University Health Network, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.; Filho SNM; University Health Network, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.; Li M; University Health Network, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.; Fares A; University Health Network, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Department of Medicine, University of Toronto, Toronto, Ontario, Canada.; Weiss J; University Health Network, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.; Pham NA; University Health Network, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.; Ludkovski O; University Health Network, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.; Raghavan V; University Health Network, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.; Li Q; University Health Network, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.; Ravi D; University Health Network, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.; Cabanero M; University Health Network, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.; Moghal N; University Health Network, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.; Leighl NB; University Health Network, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Department of Medicine, University of Toronto, Toronto, Ontario, Canada.; Bradbury P; University Health Network, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Department of Medicine, University of Toronto, Toronto, Ontario, Canada.; Sacher A; University Health Network, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Department of Medicine, University of Toronto, Toronto, Ontario, Canada.; Shepherd FA; University Health Network, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Department of Medicine, University of Toronto, Toronto, Ontario, Canada.; Yasufuku K; University Health Network, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Department of Surgery, University of Toronto, Toronto, Ontario, Canada.; Tsao MS; University Health Network, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. Electronic address: ming.tsao@uhn.ca.; Liu G; University Health Network, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Dalla Lana School of Public Health and Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
Source
Publisher: Elsevier Scientific Publishers Country of Publication: Ireland NLM ID: 8800805 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1872-8332 (Electronic) Linking ISSN: 01695002 NLM ISO Abbreviation: Lung Cancer Subsets: MEDLINE
Subject
Language
English
Abstract
Background: Anaplastic lymphoma kinase (ALK) targeted therapies have demonstrated remarkable efficacy in ALK-positive lung adenocarcinomas. However, patients inevitably develop resistance to such therapies. To investigate novel mechanisms of resistance to second generation ALK inhibitors, we characterized and modeled ALK inhibitor resistance of ALK-positive patient-derived xenograft (PDX) models established from advanced-stage lung adenocarcinoma patients who have progressed on one or more ALK inhibitors.
Methods: Whole exome sequencing was performed to identify resistance mechanisms to ALK inhibitors in PDXs generated from biopsies at the time of relapse. ALK fusion status was confirmed using fluorescent in situ hybridization, immunohistochemistry, RNA-sequencing, RT-qPCR and western blot. Targeted therapies to overcome acquired resistance were then tested on the PDX models.
Results: Three PDX models were successfully established from biopsies of two patients who had progressed on crizotinib and/or alectinib. The PDX models recapitulated the histology and ALK status of their patient tumors, as well as their matched patients' clinical treatment outcome to ALK inhibitors. Whole exome sequencing identified MET amplification and previously unreported BRAF V600E mutation as independent mechanisms of resistance to alectinib. Importantly, PDX treatment of inhibitors specific for these targets combined with ALK inhibitor overcame resistance.
Conclusions: Bypass signaling pathway through c-MET and BRAF are independent mechanisms of resistance to alectinib. Individualized intervention against these resistance pathways could be viable therapeutic options in alectinib-refractory lung adenocarcinoma.
Competing Interests: Declaration of Competing Interest Dr. Liu is a consultant or has received honoraria for advisory boards and educational sessions from AstraZeneca, Takeda, Roche, Merck, Bayer, Novartis, Pfizer, EMD Serono, Boehringer Ingelheim, Bristol Myers Squibb. Research funding to Dr. Liu’s institution from AstraZeneca, Takeda, Roche, and Boehringer Ingelheim. The remaining authors have nothing to disclose.
(Copyright © 2020 Elsevier B.V. All rights reserved.)
Methods: Whole exome sequencing was performed to identify resistance mechanisms to ALK inhibitors in PDXs generated from biopsies at the time of relapse. ALK fusion status was confirmed using fluorescent in situ hybridization, immunohistochemistry, RNA-sequencing, RT-qPCR and western blot. Targeted therapies to overcome acquired resistance were then tested on the PDX models.
Results: Three PDX models were successfully established from biopsies of two patients who had progressed on crizotinib and/or alectinib. The PDX models recapitulated the histology and ALK status of their patient tumors, as well as their matched patients' clinical treatment outcome to ALK inhibitors. Whole exome sequencing identified MET amplification and previously unreported BRAF V600E mutation as independent mechanisms of resistance to alectinib. Importantly, PDX treatment of inhibitors specific for these targets combined with ALK inhibitor overcame resistance.
Conclusions: Bypass signaling pathway through c-MET and BRAF are independent mechanisms of resistance to alectinib. Individualized intervention against these resistance pathways could be viable therapeutic options in alectinib-refractory lung adenocarcinoma.
Competing Interests: Declaration of Competing Interest Dr. Liu is a consultant or has received honoraria for advisory boards and educational sessions from AstraZeneca, Takeda, Roche, Merck, Bayer, Novartis, Pfizer, EMD Serono, Boehringer Ingelheim, Bristol Myers Squibb. Research funding to Dr. Liu’s institution from AstraZeneca, Takeda, Roche, and Boehringer Ingelheim. The remaining authors have nothing to disclose.
(Copyright © 2020 Elsevier B.V. All rights reserved.)