MET activation via exon 14 skipping mutations (METex14del): gastrointestinal prevalence and sensitivity to MET inhibitor AMG337

Date 29 June 2016
Event ESMO World Congress on Gastrointestinal Cancer 2016
Session ESMO World Congress on Gastrointestinal Cancer 2016 - Abstracts book
Presenter F. Cecchi
Citation Annals of Oncology (2016) 27 (2): 1-85. 10.1093/annonc/mdw199
Authors F. Cecchi1, S. Rabizadeh2, P. Weingarten3, C. Tsai4, L. Zhou3, T. Hembrough1
  • 1NantOmics, Rockville, Maryland, USA, /
  • 2NantOmics, Culver City, California, USA, /
  • 3Nantbio, Culver City, California, USA, /
  • 4Nanbio, Culver City, California, USA, /

Abstract

Activation of the MET oncogene can result from amplification or activating mutation. MET mutations affecting the 14 5' splice acceptor site or the 3' splice donor site cause in-frame skipping of exon 14. The resulting protein lacks a portion of the juxtamembrane domain, which eliminates binding of Cbl, an E3 ubiquitin ligase involved in Met down-regulation. Met protein lacking exon 14 results in a relative over-expression of Met protein, MET activation and oncogenesis. Case reports are the only clinical evidence of response to MET inhibitors in patients harboring METex14del. To date, partial responses have been reported in 13 cases of lung cancer cases treated with MET inhibitors; the duration of response ranged from 5 weeks to >13 months. In these reports, treatment with MET inhibitors decreased the size of tumors throughout the body, including a metastatic lesion in the brain. The ongoing crizotinib trial that led to approval of crizotinib for ALK- and ROS1-rearranged non-small cell lung cancer is now enrolling patients with METex14del. METex14del has been identified in gastric cancer cell lines and in RNA extracted from patients with gastric cancer (3/42;7%) and colon cancer (4/43;9%). Here we report that the small-molecule MET inhibitor AMG 337 demonstrates nanomolar inhibition of the Met kinase activity in gastric cell lines harboring METex14del.