Molecular heterogeneity and receptor coamplification drive resistance to targeted therapy in MET-Amplified esophagogastric cancer

Eunice L. Kwak, Leanne G. Ahronian, Giulia Siravegna, Benedetta Mussolin, Jason T. Godfrey, Jeffrey W. Clark, Lawrence S. Blaszkowsky, David P. Ryan, Jochen K. Lennerz, A. John Iafrate, Alberto Bardelli, Theodore S. Hong, Ryan B. Corcoran

Research output: Contribution to journalArticlepeer-review

Abstract

MET inhibition is effective in some patients with MET -amplified esophagogastric cancer (EGC), but understanding acquired and de novo resistance mechanisms will be critical to improving therapy. We identified KRAS mutation as a novel cause of acquired resistance in a patient after a 2-year response to a MET inhibitor. We also observed that 40% to 50% of patients with MET -amplified EGC harbor coamplification of HER2 and/or EGFR concurrently in the same tumor cells, which can drive de novo resistance. One patient with concurrent MET and HER2 amplification was refractory to HER2 blockade, but responded to combined MET/HER2 inhibition. We also found striking heterogeneity in MET amplification between distinct metastatic lesions and primary tumors in individual patients with EGC. In these patients, MET inhibition led to mixed responses and disease progression through outgrowth of non–MET-amplified clones, which could be monitored in circulating tumor DNA. Thus, receptor coamplification and molecular heterogeneity may be key drivers of clinical resistance in MET -amplified EGC. Significance: Coamplification of driver oncogenes occurs frequently in EGC and can drive therapeutic resistance, supporting a role for comprehensive molecular analysis prior to targeted therapy. EGCs can also exhibit extensive heterogeneity in gene amplification between distinct tumor lesions within the same patient, suggesting that molecular profiling of a single-lesion biopsy may be insufficient to guide targeted therapy selection.

Original languageEnglish
Pages (from-to)1271-1281
Number of pages11
JournalCancer Discovery
Volume5
Issue number12
DOIs
Publication statusPublished - Dec 1 2015

ASJC Scopus subject areas

  • Oncology

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