Using a primary culture derived from a HER2-non-amplified MET (N375S) heterozygous tongue SCC tumor (NCC-NPC7), we confirmed the increased susceptibility to HER2 inhibitors (lapatinib and afatinib), but not to crizotinib as compared to a HER2-non-amplified MET wild-type HNSCC cell line (SCC13) (Supplementary Fig. 9A). Mechanistically, crizotinib attenuated p-MET and p-Src while not affecting other kinases in NPC7 cells (Supplementary Fig. 9B). On the contrary, treatment with lapatinib and afatinib effectively abrogated kinase activities of HER2, EGFR, Akt, and ERK1/2 (Supplementary Fig. 9B). In addition, we confirmed that METN375S variant in NCC-NPC7 cells co-immunoprecipitated with HER2, and similar to that in isogenic H2170 cells (Fig. 5a), this interaction could be abolished by kinase inhibition through crizotinib or/and lapatinib treatment (Supplementary Fig. 9C). Importantly, afatinib given at 15 mg/kg daily was found to significantly improve overall survival (log-rank test; P < 0.05) over the vehicle control in immunocompromised mice engrafted with METN375S-tGFP cells (Fig. 6o). In contrast, mice engrafted with METwt-tGFP cells survived longer and did not benefit from afatinib treatment (Fig. 6n), thereby confirming the aggressiveness of N375S tumors as well as the therapeutic potential of pharmacological HER2 inhibition in these tumors.
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