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

Abstract

Background: 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. Methods:GermlineDNA (gDNA) of lung, nasopharyngeal, liver, breast, gastric and colon cancer cohorts among East Asians (n=1,076) were genotyped forMET (p.N375S) polymorphismusing 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 enrollingMET-N375S+ squamous cell (SCC) head and neck patients to be given 30mg afatinib daily. Treatment outcome was determined with F-FDGPET/CT scan. Baseline (BL) and post-treatment biopsies were analyzed with immunohistochemistry for response biomarkers and in situ hybridizationproximity ligation assay (ISH-PLA) for receptor interaction. Results: 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<0.05). Two patients with refractory HNSCC who completed 1 cycle of afatinib, a pan-HER inhibitor, showed radiological tumour shrinkage and reduction in metabolic activity, with partial response by RECIST 1.1 measurement observed in one patient. Evaluable BL biopsy showed strong MET-HER2 interaction (ISH-PLA) with strong staining of phosphorylated MET and HER2 (IHC), which were significantly reduced post-treatment, indicative of successive intervention of MET-N375S/HER2 signaling. Conclusions: We established MET-N375S as a biologically-distinct molecular subset of SCC that drives malignancy through HER2 signaling, and could serve as a predictive biomarker to select refractory patients with dismal prognosis for afatinib treatment.