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Mechanisms of Acquired Resistance to Savolitinib, a Selective MET Inhibitor in MET-Amplified Gastric Cancer.

ABSTRACT: PURPOSE:Some gastric cancers harbor MET gene amplifications that can be targeted by selective MET inhibitors to achieve tumor responses, but resistance eventually develops. Savolitinib, a selective MET inhibitor, is beneficial for treating patients with MET-driven gastric cancer. Understanding the resistance mechanisms is important for optimizing postfailure treatment options. PATIENTS AND METHODS:Here, we identified the mechanisms of acquired resistance to savolitinib in 3 patients with gastric cancer and MET-amplified tumors who showed a clinical response and then cancer progression. Longitudinal circulating tumor DNA (ctDNA) is useful for monitoring resistance during treatment and progression when rebiopsy cannot be performed. RESULTS:Using a next-generation sequencing 100-gene panel, we identified the target mechanisms of resistance MET D1228V/N/H and Y1230C mutations or high copy number MET gene amplifications that emerge when resistance to savolitinib develops in patients with MET-amplified gastric cancer. CONCLUSION:We demonstrated the utility of ctDNA in gastric cancer and confirmed this approach using baseline tumor tissue or rebiopsy.

SUBMITTER: Frigault MM 

PROVIDER: S-EPMC7446425 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Mechanisms of Acquired Resistance to Savolitinib, a Selective MET Inhibitor in <i>MET</i>-Amplified Gastric Cancer.

Frigault Melanie M MM   Markovets Aleksandra A   Nuttall Barrett B   Kim Kyoung-Mee KM   Park Se Hoon SH   Gangolli Esha A EA   Mortimer Peter G S PGS   Hollingsworth Simon J SJ   Hong Jung Yong JY   Kim Kyung K   Kim Seung Tae ST   Barrett J Carl JC   Lee Jeeyun J  

JCO precision oncology 20200324

<h4>Purpose</h4>Some gastric cancers harbor <i>MET</i> gene amplifications that can be targeted by selective MET inhibitors to achieve tumor responses, but resistance eventually develops. Savolitinib, a selective MET inhibitor, is beneficial for treating patients with MET-driven gastric cancer. Understanding the resistance mechanisms is important for optimizing postfailure treatment options.<h4>Patients and methods</h4>Here, we identified the mechanisms of acquired resistance to savolitinib in 3  ...[more]

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