Dataset Information

MET Alterations Are a Recurring and Actionable Resistance Mechanism in ALK-Positive Lung Cancer.

ABSTRACT:

Purpose

Most ALK-positive lung cancers will develop ALK-independent resistance after treatment with next-generation ALK inhibitors. MET amplification has been described in patients progressing on ALK inhibitors, but frequency of this event has not been comprehensively assessed.

Experimental design

We performed FISH and/or next-generation sequencing on 207 posttreatment 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 antitumor activity of ALK/MET blockade in ALK-positive cell lines and 2 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 ALK inhibitor in the first-line setting were more likely to develop MET amplification than those who had received next-generation ALK inhibitors after crizotinib (P = 0.019). Two tumor specimens harbored an identical 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 resensitized 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 rapid responses to ALK/MET combination therapy.

Conclusions

Treatment with next-generation ALK inhibitors, particularly in the first-line setting, may lead to MET-driven resistance. Patients with acquired MET alterations may derive clinical benefit from therapies that target both ALK and MET.

SUBMITTER: Dagogo-Jack I

PROVIDER: S-EPMC7269872 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Publications

MET Alterations Are a Recurring and Actionable Resistance Mechanism in ALK-Positive Lung Cancer.

Dagogo-Jack Ibiayi I Yoda Satoshi S Lennerz Jochen K JK Langenbucher Adam A Lin Jessica J JJ Rooney Marguerite M MM Prutisto-Chang Kylie K Oh Audris A Adams Nathaniel A NA Yeap Beow Y BY Chin Emily E Do Andrew A Marble Hetal D HD Stevens Sara E SE Digumarthy Subba R SR Saxena Ashish A Nagy Rebecca J RJ Benes Cyril H CH Azzoli Christopher G CG Lawrence Michael S MS Gainor Justin F JF Shaw Alice T AT Hata Aaron N AN

Clinical cancer research : an official journal of the American Association for Cancer Research 20200221 11

<h4>Purpose</h4>Most <i>ALK</i>-positive lung cancers will develop ALK-independent resistance after treatment with next-generation ALK inhibitors. <i>MET</i> amplification has been described in patients progressing on ALK inhibitors, but frequency of this event has not been comprehensively assessed.<h4>Experimental design</h4>We performed FISH and/or next-generation sequencing on 207 posttreatment tissue (<i>n</i> = 101) or plasma (<i>n</i> = 106) specimens from patients with ALK-positive lung c ...[more]

PMID: 32086345

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Project description:Patient-led advocacy organizations in the anaplastic lymphoma kinase (ALK)-positive lung cancer space are becoming increasingly influential. ALK Positive Inc. (hereafter "ALK Positive") is probably the most widely known among these organizations. Evolving from a private Facebook Support Group created in 2015 to provide a forum for ALK-positive lung cancer patients and caregivers to exchange information, empathy and support, ALK Positive transitioned in 2021 into a 501(c)(3) non-profit organization (NPO), with the mission to improve the life expectancy and quality of life for ALK-positive cancer patients worldwide. This review provides a historical perspective on the growth, activities and aspirations of ALK Positive to pursue patient advocacy and enable development of new therapies for individuals with ALK-positive cancers. This growth has been enabled by the collaborative efforts of ALK-positive cancer patients, their care-partners and oncologists, academic researchers, other NPO advocacy organizations, and members of the biotech and pharma communities who develop new therapies for ALK-positive cancers. ALK Positive has grown to provide a variety of patient services, to award competitive support for translational research and clinical trials intended to enable new therapies and improved quality and extent of life for ALK-positive cancer patients, and to collaborate with industry and academia to accelerate the development of improved therapies for ALK-positive cancer patients. ALK Positive continues grappling with a variety of challenges including further improving patient quality of life, enabling the development of new therapies, and extending its already substantial global reach and impact. This review summarizes many of the tangible impacts and aspirations engendered by ALK Positive for ALK-positive cancer patients in the past, present and future tenses-where we have been, where we stand and where we hope to go. The content is based on the historical recollections of the authors, and is accurate as of November 30, 2022, to the best of the authors' knowledge.

Dataset Information

MET Alterations Are a Recurring and Actionable Resistance Mechanism in ALK-Positive Lung Cancer.

Purpose

Experimental design

Results

Conclusions

Publications

MET Alterations Are a Recurring and Actionable Resistance Mechanism in ALK-Positive Lung Cancer.

Similar Datasets

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