1959P - HER2 inhibition in aggressive squamous cell carcinomas driven by a common MET sema domain polymorphism

Oncogenic MET signaling is often deployed by tumors for malignant transformation through genomic events like tyrosine kinase domain mutations, juxtamembrane splicing mutation and amplified copy numbers, which can be inhibited by c-MET small molecule inhibitors. We present biochemical and clinical findings on a polymorphism of MET, which is common in the East Asian population. Germline DNA (gDNA) of lung, nasopharyngeal, liver, breast, gastric and colon cancer cohorts among East Asians (n=1,076) were genotyped for MET (p.N375S) polymorphism using digital droplet PCR (ddPCR). Relapse free survival (RFS) with curative intent was compared using log-rank test. Screening for protein-protein interaction was performed with SILAC. Clinical study is now enrolling MET-N375S+ squamous cell (SCC) head and neck patients to be given 30mg afatinib daily. Treatment outcome was determined with F-FDG PET/CT scan. Baseline (BL) and post-treatment biopsies were analyzed with immunohistochemistry for response biomarkers and in situ hybridization-proximity ligation assay (ISH-PLA) for receptor interaction. Fraction of the MET-N375S+ cases is comparable across cancer patients and cancer-free controls (9-18%). METN375S was associated with significantly shorter relapse-free survival (RFS) in SCC of the head and neck (HNSCC; P=0.005) and lung (LUSC; P=0.029). SILAC revealed interaction of MET-N375S with HER2 (P