Abstract 1118: Activation of MET via diverse exon 14 skipping mutations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors
Authors: Frampton Garrett M. , Ali Siraj , Chmielecki Juliann , Rosenzweig Mark , Brennan Timothy , Chalmers Zachary , Elvin Julia , Fichtenholtz Alex , Gowan Kyle , Greenbowe Joel , Johnson Adrienne , Khaira Lily , Lipson Doron , McMahon Caitlin , Roels Steven , Yelensky Roman , Morosini Deborah , Stephens Philip , Miller Vincent 
Published: August 2015

Abstract
Amplification and point mutation in MET are well-characterized oncogenic drivers that confer susceptibility to MET inhibitors, such as crizotinib, particularly in non-small cell lung cancer. Splice site alterations at exon 14 of the MET (METex14) gene result in exon skipping and MET activation through loss of a DpYR motif (Y1003) that recruits the ubiquitin ligase CBL, targeting MET for degradation. METex14 skipping mutations have primarily been detected in lung adenocarcinoma, occurring in ∼3% of cases, but also in neuroblastoma and gastric cancer cell lines. 17 distinct variants have been characterized, however, their full diversity and prevalence across tumor types is unknown. Most importantly, it is unknown whether these mutations confer clinical susceptibility to targeted therapy with multiple MET inhibitors.
We report here analysis of 29,714 cancer genomes to identify 168 harboring METex14 splicing mutations, including 101 distinct genomic variants. They are detected most frequently in lung adenocarcinoma (3.1%, 104/3360), but also in other lung neoplasms (2.0%, 40/2022), brain glioma (0.5%, 6/1312), tumors of unknown primary origin (0.4%, 11/2516), and other tumor types (0.03% 7/20504). Lung malignancies with these mutations do not have other characteristic driver mutations, and have a distinct profile of co-occurring mutations, supporting the role of METex14 skipping as the primary drivers of oncogenesis in these specimens. Most importantly, patients with tumors harboring these mutations demonstrate durable response to anti-MET targeted therapy, in several tumor types.
These data demonstrate that METex14 splicing mutations define a distinct class of tumors that are responsive to targeted therapy. The diversity of these variants indicates that diagnostic testing via massively parallel sequencing is necessary for detection in a clinical setting. The data also suggest that thousands of cancer genome profiles will be required to discover non-coding cancer drivers with degenerate genomic signatures.
Citation Format: Garrett M. Frampton, Siraj Ali, Juliann Chmielecki, Mark Rosenzweig, Timothy Brennan, Zachary Chalmers, Julia Elvin, Alex Fichtenholtz, Kyle Gowan, Joel Greenbowe, Adrienne Johnson, Lily Khaira, Doron Lipson, Caitlin McMahon, Steven Roels, Roman Yelensky, Deborah Morosini, Philip Stephens, Vincent Miller. Activation of MET via diverse exon 14 skipping mutations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1118. doi:10.1158/1538-7445.AM2015-1118