Combinatorial approaches targeting the EGFR family and c-Met in SCCHN. (January 2021) - Wang, Dongsheng
Highlights: Three different c-Met inhibitors in combination with a pan-HER inhibitor were investigated for their anti-tumor effects on SCCHN cell lines in vitro . In vivo studies on SCCHN cell line xenograft and patient derived xenograft (PDX) animal models from patients with recurrent squamous cell carcinoma of the head and neck were also carried out for the three combinations. A ctivation of EGFR, HER2, HER3, and c-Met was blocked and the downstream PI3K/AKT and ERK signaling pathways were inhibited. Simultaneous targeting of EGFR, HER2, and c-Met is more effective than the individual inhibition of these targets in vitro and in SCCHN cell line xenograft and PDX models. Abstract: Objective: We aimed to develop novel combinations of inhibitors targeting EGFR family members and c-Met for the treatment of recurrent SCCHN. Materials and Methods: Three different c-Met inhibitors in combination with a pan-HER inhibitor (crizotinib/afatinib, tivantinib/afatinib and cabozantinib/afatinib) were investigated for their anti-tumor effects on SCCHN cell lines in vitro . In vivo activity of the combinations was tested in SCCHN cell line xenografts and patient-derived xenograft (PDX) animal models generated from patients with recurrent SCCHN. Results: Western blot assay indicated that activation of EGFR, HER2, HER3, and c-Met was blocked by all three combinations and the downstream PI3K/AKT and ERK signaling pathways were inhibited. Sulforhodamine B colorimetric assay revealed SCCHN cell growth was more effectively inhibited by the combinations than by single agents, particularly in cell lines with high c-Met expression. Furthermore, the combinations were more potent in inducing apoptosis than each of the single agents. In the PDX models, the combination treatments exhibited significantly better efficacy in tumor growth inhibition compared to the respective single agents. Conclusion: In conclusion, we demonstrated that the simultaneous targeting of EGFR, HER2, and c-Met is more effective than the individual inhibition of these targets in vitro and in SCCHN cell line xenograft and PDX models. Our findings pave the way for further clinical investigation of such combinations in SCCHN.