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E. Collisson
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P2.03b - Poster Session with Presenters Present (ID 465)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.03b-042 - MET exon 14 Mutations Encode a Hyperactive Kinase and Therapeutic Target in Lung Adenocarcinoma (ID 5252)
14:30 - 14:30 | Author(s): E. Collisson
- Abstract
Background:
Activation of the MET tyrosine kinase receptor can drive oncogenesis and metastasis in certain cancer types. Somatic mutations at or around the splice junctions for MET exon 14 (METΔ14) are a recurrent mechanism of MET activation. METΔ14 mutations lead to aberrant messenger RNA (mRNA) splicing resulting in a METΔ14 protein lacking the juxtamembrane domain.
Methods:
We analyzed RNAseq data across 12 cancer types to define the prevalence of METΔ14 in solid tumors. We explored the driver role of METΔ14 both in vitro and in vivo. Finally, we explored acquired resistance mechanisms in a patient treated with crizotinib.
Results:
The METΔ14 mutation and aberrant mRNA transcript are most common in lung adenocarcinoma and also identified in other cancers. Endogenous levels of METΔ14 transcript transform human epithelial lung cells in an HGF-dependent manner. This allele also induces lung cancer in mice that is responsive to a clinically available MET inhibitor. Finally, we document clinical response to crizotinib in a patient with a METΔ14-driven NSCLC lung cancer. Upon clinical progression on crizotinib, indicating acquired resistance, we detected acquired MET mutations in cell-free DNA from the patient that converge on critical drug-binding residues in the MET activation loop.
Conclusion:
These findings qualify METΔ14 mutations as drivers of lung adenocarcinoma, deomstrate the utility of a new animal model of MET-driven disease and identify a subpopulation of patients who may benefit from further development of targeted MET/HGF therapies.
