Background

The DpY motif within the exon 14 juxta-membrane domain of the MET receptor gene is a critical regulatory site on the MET gene, specifically, where Cbl docks to mediate 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 (actual Cbl docking site) are thought to lead to similar effects as ex14sk, but due to their rarity, their role in NSCLC is unknown.

Methods:

Retrospective review of molecular profiles for non-ex14sk mt that include/surround the DpY motif (Y1021) in MET. Numbers updated since ASCO abstract submision. Two NGS platforms were included: MiSeq (2014-2017; n = 2865) and NextSeq (2017-2019; n = 7963). Immunohistochemistry (IHC) of cMET (SP44) and co-occurring alterations (EGFR, KRAS, ALK, ROS, etc.) were also reviewed.

Conclusions

• MET exon 14 analog mutations are rare events occurring at a frequency of 0.1%
• Similar to patients with exon 14 skipping mutations, 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 exon 14 skipping mutations suggests deletions of exon 14 provide cellular advantages beyond Cblmediated ubiquitinylation of MET.
• Although rare, the impact of these mutations on efficacy of Met-directed therapy deserves further exploration.
• Further studies comparing MET exon 14 skipping mutants, analogs and other exon 14 mutants may provide more insight into the underlying biology and contribution of additional regulatory sites upstream of Y1021, including the PKC phosphorylation site and Caspase cleavage sites