MET exon 14 skipping analogs: Rare but potentially clinically actionable.

Abstract

3141 Background: The DpY motif within the exon 14 juxtamembrane domain of the MET receptor gene is critical for Cbl-mediated negative regulation. Splicing alterations that delete this residue, known as exon 14 skipping mutations (ex14sk mt), lead to prolonged MET protein stability and oncogenic signaling. Specific mt at the Y1021 (aka 1003) residue are thought to lead to similar effects as ex14sk, but due to their rarity, their role in NSCLC is unknown. We sought to identify and characterize non-ex14sk mt that include/surround Y1021. Methods: Retrospective review of molecular profiles for non-ex14sk mt that include/surround the DpY motif (Y1021) in MET. Two NGS platforms were included: MiSeq (2014-2017; n=2865) and NextSeq (2017-2019; n=6084). Immunohistochemistry (IHC) of cMET (SP44) and co-occurring alterations (EGFR, KRAS, ALK, ROS) were also reviewed. Results: Of 8,949 NSCLC patients with successful NGS of MET gene by either platform, 13 cases or 0.2% were identified to have an alteration within the amino acids of interest. Eleven cases included substitutions at Y1021 (5 phenylalanine, 4 histidine and 3 arginine) and the remaining two cases included small insertion-deletions p.E1017_Y1021delinsH and p.D1020_Y1021delinsV, the latter was later excluded as it co-harbored an ex14sk mt. Conclusions: Similar to patients with ex14sk mt, substitutions and small indels at Y1021 exhibit Clinicopathological features such as previous smoking history and older age, mutual exclusivity with oncogene drivers and MET protein overexpression. The rarity of these analogous ex14sk mt suggests deletions of exon 14 provide cellular advantages beyond Cbl-mediated ubiquitinylation of MET. Although rare, the impact of these mt on efficacy of Met-directed therapy deserves further exploration.[Table: see text]