MET Alterations Are a Recurring and Actionable Resistance Mechanism in ALK-Positive Lung Cancer
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- 21 February 2020
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Clinical Cancer Research
- Vol. 26 (11), 2535-2545
- https://doi.org/10.1158/1078-0432.ccr-19-3906
Abstract
Background: Most ALK-positive lung cancers will develop ALK-independent resistance after treatment with ALK inhibitors. MET amplification has been described in patients progressing on ALK inhibitors, but frequency of this event has not been comprehensively assessed. Methods: We performed fluorescence in-situ hybridization and/or next-generation sequencing on 207 post-treatment tissue (n=101) or plasma (n=106) specimens from patients with ALK-positive lung cancer to detect MET genetic alterations. We evaluated ALK inhibitor sensitivity in cell lines with MET alterations and assessed activity of ALK/MET blockade in ALK-positive cell lines and two patients with MET-driven resistance. Results: MET amplification was detected in 15% of tumor biopsies from patients relapsing on next-generation ALK inhibitors, including 12% and 22% of biopsies from patients progressing on second-generation inhibitors or lorlatinib, respectively. Patients treated with a second-generation inhibitor in the first-line setting were more likely to develop MET amplification than those who received next-generation ALK inhibitors after crizotinib (p=0.019). Two tumor specimens harbored an ST7-MET rearrangement, one of which had concurrent MET amplification. Expressing ST7-MET in the sensitive H3122 ALK-positive cell line induced resistance to ALK inhibitors that was reversed with dual ALK/MET inhibition. MET inhibition re-sensitized a patient-derived cell line harboring both ST7-MET and MET amplification to ALK inhibitors. Two patients with ALK-positive lung cancer and acquired MET alterations achieved responses to ALK/MET combination therapy. Conclusions: Treatment with next-generation ALK inhibitors, particularly in the first-line setting, may select for MET-driven resistance. Patients with acquired MET alterations may derive clinical benefit from therapies that target both ALK and MET.Keywords
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Funding Information
- Conquer Cancer
- Amgen Young Investigator Award
- American Cancer Society
- NCI Career Development Award (K12CA087723-16)
- Lung Cancer Research Foundation
- Conquer Cancer
- AstraZeneca Young Investigator Award
- NCI (R01CA164273, R01CA225655)
- Cure for Lung Cancer Research Fund
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