Molecular heterogeneity and receptor co-amplification drive resistance to targeted therapy in MET-amplified esophagogastric cancer

MET inhibition is effective in some MET -amplified esophagogastric cancer (EGC) patients, 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 two-year response to MET inhibitor. We also observed that 40–50% of MET -amplified EGC patients harbor co-amplification 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 EGC patients. 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 co-amplification and molecular heterogeneity may be key drivers of clinical resistance in MET -amplified EGC.