Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore.
Medical Research Council Cancer Unit, University of Cambridge, Cambridge, CB2 0XZ, UK.
Nat Commun. 2020 Mar 25;11(1):1556. doi: 10.1038/s41467-020-15318-5.
c-MET receptors are activated in cancers 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. Here, we discover that the most common polymorphism known to affect MET gene (N375S), involving the semaphorin domain, confers exquisite binding affinity for HER2 and enables MET to interact with HER2 in a ligand-independent fashion. The resultant MET/HER2 dimer transduces potent proliferative, pro-invasive and pro-metastatic cues through the HER2 signaling axis to drive aggressive squamous cell carcinomas of the head and neck (HNSCC) and lung (LUSC), and is associated with poor prognosis. Accordingly, HER2 blockers, but not c-MET inhibitors, are paradoxically effective at restraining in vivo and in vitro models expressing MET. These results establish MET as a biologically distinct and clinically actionable molecular subset of SCCs that are uniquely amenable to HER2 blocking therapies.
c-MET 受体通过酪氨酸激酶结构域突变、跨膜区剪接突变和扩增拷贝数等基因组事件在癌症中被激活，这些可以被 c-MET 小分子抑制剂抑制。在这里，我们发现已知最常见的影响 MET 基因（N375S）的多态性，涉及到信号素结构域，赋予了 MET 与 HER2 极高的结合亲和力，并使 MET 以配体非依赖性的方式与 HER2 相互作用。由此产生的 MET/HER2 二聚体通过 HER2 信号通路传递强烈的增殖、侵袭和转移信号，从而驱动头颈部鳞状细胞癌（HNSCC）和肺癌（LUSC）的侵袭性生长，并与预后不良相关。因此，HER2 阻断剂，而不是 c-MET 抑制剂，在体内和体外模型中表达 MET 时具有出乎意料的抑制效果。这些结果确立了 MET 作为 SCC 中具有生物学差异和临床可操作性的分子亚群，对 HER2 阻断治疗具有独特的适应性。
