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.
- Received June 19, 2015.
- Revision received September 24, 2015.
- Accepted September 29, 2015.
- Copyright © 2015, American Association for Cancer Research.