Combinatorial approaches targeting the EGFR family and c-Met in SCCHN.
Combinatorial approaches targeting the EGFR family and c-Met in SCCHN.
复制标题
SCCHN 中针对 EGFR 家族和 c-Met 的组合方法。
DOI：
10.1016/j.oraloncology.2020.105074
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发表时间：
2021
期刊：
影响因子：
4.8
通讯作者：
Saba,NabilF
中科院分区：
文献类型：
--
作者：
Wang,Dongsheng;Lu,Yue;Nannapaneni,Sreenivas;Griffith,ChristopherC;Steuer,Conor;Qian,Guoqing;Wang,Xu;Chen,Zhengjia;Patel,Mihir;El-Deiry,Mark;Shin,DongM;He,Xia;Chen,ZhuoG;Saba,NabilF
ObjectiveWe aimed to develop novel combinations of inhibitors targeting EGFR family members and c-Met for the treatment of recurrent SCCHN.Materials and MethodsThree 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 linesin vitro.In vivoactivity of the combinations was tested in SCCHN cell line xenografts and patient-derived xenograft (PDX) animal models generated from patients with recurrent SCCHN.ResultsWestern 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.ConclusionIn conclusion, we demonstrated that the simultaneous targeting of EGFR, HER2, and c-Met is more effective than the individual inhibition of these targetsin vitroand in SCCHN cell line xenograft and PDX models. Our findings pave the way for further clinical investigation of such combinations in SCCHN.
