A common MET polymorphism harnesses HER2 signaling to drive aggressive squamous cell carcinoma

Li Ren Kong ,Nur Afiqah Binte Mohamed Salleh ,Robby Miguel Goh,Hung Huynh ,Srinivasaraghavan Kannan,Ross A Soo ,H Phillip Koeffler,Benedict Yan ,Seng Gee Lim,Chee Wai Fhu,Min En Nga,Jingshan Ho,N Gopalakrishna Iyer,Chandra Verma ,Tuan Zea Tan,Daniel S.w Tan ,Richard Ong ,Soo‐Chin Lee ,Yong Ching Lim ,Nicholas Syn ,Dennis Kappei,Yiqing Huang,Joline Si Jing Lim ,Boon Cher Goh

doi:10.1038/s41467-020-15318-5

Abstract

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.

Highlights

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
We genotyped the METN375S variant in germline DNA of several cohorts of patients (n = 1076) diagnosed with common cancers in the East Asian population in relation to healthy cancer-free controls, and determined the prevalence of the N375S polymorphism to be comparable in cancer patients relative to healthy, cancer-free controls (Fig. 1a, b)
The relapse-free survival (RFS) was significantly shorter in patients with the METN375S polymorphism in both the SCC cohorts (Fig. 1c, d), suggesting a more aggressive oncogenic phenotype associated with this MET variant

Summary

Introduction

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. 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. The Sema domain plays an essential function in ligand binding and receptor dimerization[16], but its role in cancer cells is not well delineated. We characterize the biologically- and clinically aggressive phenotype driven by METN375S in LUSC and HNSCC, elucidate the intriguing mechanism by which METN375S co-opts HER2 signaling to drive SCCs, and crucially, translate our findings into therapeutically cogent interventions with the successful therapy of tumor-bearing animals using commerciallyavailable HER2 inhibitors. Our results provide a strong clinical foundation for treating METN375S SCC patients with HER2-targeted therapies

Methods

Results

Conclusion