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A common MET polymorphism harnesses HER2 signaling to drive aggressive squamous cell carcinoma.
Nature Communications ( IF 16.6 ) Pub Date : 2020-03-25 , DOI: 10.1038/s41467-020-15318-5
Li Ren Kong 1, 2 , Nur Afiqah Binte Mohamed Salleh 1 , Richard Weijie Ong 3 , Tuan Zea Tan 1 , Nicholas L Syn 1, 4 , Robby Miguel Goh 4 , Chee Wai Fhu 1 , Daniel S W Tan 5, 6, 7 , N Gopalakrishna Iyer 1, 8, 9 , Srinivasaraghavan Kannan 10 , Chandra S Verma 10, 11, 12 , Yaw Chyn Lim 13 , Ross Soo 4 , Jingshan Ho 4 , Yiqing Huang 4 , Joline S J Lim 1, 4 , Benedict Junrong Yan 13 , Min En Nga 13 , Seng Gee Lim 14, 15 , H Phillip Koeffler 1, 4, 14, 16 , Soo Chin Lee 1, 4 , Dennis Kappei 1 , Huynh The Hung 3 , Boon Cher Goh 1, 4, 17
Affiliation  

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 METN375S to interact with HER2 in a ligand-independent fashion. The resultant METN375S/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 METN375S. These results establish METN375S as a biologically distinct and clinically actionable molecular subset of SCCs that are uniquely amenable to HER2 blocking therapies.



中文翻译:

常见的MET多态性利用HER2信号来驱动侵袭性鳞状细胞癌。

c-MET受体在癌症中通过酪氨酸激酶结构域突变,近膜剪接突变和扩增的拷贝数等基因组事件而被激活,而c-MET小分子抑制剂可以抑制它们。在这里,我们发现已知最常见的影响MET基因(N375S)的多态性,涉及信号量域,赋予HER2精湛的结合亲和力,并使MET N375S以不依赖配体的方式与HER2相互作用。生成的MET N375S/ HER2二聚体通过HER2信号转导轴转导有效的增殖,侵袭性和转移性线索,以驱动头颈部(HNSCC)和肺部(LUSC)侵袭性鳞状细胞癌,并且预后不良。因此,HER2阻滞剂而不是c-MET抑制剂在抑制表达MET N375S的体内和体外模型方面具有反常的效果。这些结果将MET N375S确立为SCC的生物学上独特且可在临床上应用的分子亚群,其独特地适用于HER2阻断疗法。

更新日期:2020-04-24
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