MET Exon 14 Alterations in Lung Cancer: Exon Skipping Extends Half-Life

Abstract

MET exon 14 alterations are a diverse group of mutations, many of which disrupt splice acceptor or donor sites leading to exon 14 skipping, impaired receptor degradation, and oncogenic transformation. These alterations are clinically targetable with MET-directed therapy. Clin Cancer Res; 22(12); 2832-4. ©2016 AACRSee related article by Tong et al., p. 3048.

Figure 1

In this diagram, part of the MET gene is depicted on the left in Figure 1A. This portion of the gene includes exons 13, 14, and 15, and introns 13 and 14. DNA is transcribed into pre-mRNA, and introns are spliced out (orange triangles) by normal splicing mechanisms. This process involves the recognition of specific regions along the intron including as 5′ and 3′ splice sites. mRNA is eventually translated into the MET receptor protein. The transmembrane MET receptor is depicted in Figure 1A on the right. Binding of the ligand HGF (red) results in downstream pathway activation and increased cellular proliferation. MET exon 14 encodes a region on the receptor (green) that includes the Y1003 residue. This residue serves as a binding site for the E3 ubiquitin ligase CBL (purple). Ubiquitination tags the MET protein for degradation. In Figure 1B, MET mutations (yellow) that disrupt the branch point and/or 3′ splice site of intron 13, and the 5′ splice site of intron 14 result in aberrant splicing and exon 14 skipping. These mutations normally occur separately (involving a region flanking only one end of exon 14), but are shown here in aggregate for simplicity. MET exon 14 is thus excluded in mRNA that is later translated into a protein product lacking the Y1003 residue. Loss of this region leads to leads to decreased MET receptor ubiquitination by CBL. Decreased degradation results in oncogenesis driven by increased levels of MET. Of note, base substitutions involving Y1003 or exon 14 deletions that span the area encoding this residue can likewise lead to decreased MET degradation without specifically interfering with normal splicing mechanisms.