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

Li Ren Kong; Nur Afiqah Binte Mohamed Salleh; Richard Weijie Ong; Tuan Zea Tan; Nicholas L Syn; Robby Miguel Goh; Chee Wai Fhu; Daniel S W Tan; N Gopalakrishna Iyer; Srinivasaraghavan Kannan; Chandra S Verma; Yaw Chyn Lim; Ross Soo; Jingshan Ho; Yiqing Huang; Joline S J Lim; Benedict Junrong Yan; Min En Nga; Seng Gee Lim; H Phillip Koeffler; Soo Chin Lee; Dennis Kappei; Huynh The Hung; Boon Cher Goh

doi:10.1038/s41467-020-15318-5

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

Nat Commun. 2020 Mar 25;11(1):1556. doi: 10.1038/s41467-020-15318-5.

Authors

Li Ren Kong^{1

2}, Nur Afiqah Binte Mohamed Salleh³, Richard Weijie Ong⁴, Tuan Zea Tan³, Nicholas L Syn^{3

5}, Robby Miguel Goh⁵, Chee Wai Fhu³, Daniel S W Tan^{6

7

8}, N Gopalakrishna Iyer^{3

9

10}, Srinivasaraghavan Kannan¹¹, Chandra S Verma^{11

12

13}, Yaw Chyn Lim¹⁴, Ross Soo⁵, Jingshan Ho⁵, Yiqing Huang⁵, Joline S J Lim^{3

5}, Benedict Junrong Yan¹⁴, Min En Nga¹⁴, Seng Gee Lim^{15

16}, H Phillip Koeffler^{3

5

15

17}, Soo Chin Lee^{3

5}, Dennis Kappei³, Huynh The Hung⁴, Boon Cher Goh^{18

19

20}

Affiliations

¹ Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore. [email protected].
² Medical Research Council Cancer Unit, University of Cambridge, Cambridge, CB2 0XZ, UK. [email protected].
³ Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore.
⁴ Laboratory of Molecular Endocrinology, National Cancer Centre Singapore, Singapore, 169610, Singapore.
⁵ Department of Hematology-Oncology, National University Cancer Institute, Singapore, 119074, Singapore.
⁶ Cancer Therapeutics Research Laboratory, National Cancer Centre Singapore, Singapore, 169610, Singapore.
⁷ Division of Medical Oncology, National Cancer Centre Singapore, Singapore, 169610, Singapore.
⁸ Genome Institute of Singapore, Agency for Science, Technology & Research (A*STAR), Singapore, 138672, Singapore.
⁹ Office of Clinical Sciences, Duke-NUS Medical School, Singapore, 169857, Singapore.
¹⁰ Division of Surgical Oncology, National Cancer Centre Singapore, Singapore, 169610, Singapore.
¹¹ Bioinformatics Institute, Agency for Science, Technology, and Research (A*STAR), Singapore, 138671, Singapore.
¹² Department of Biological Sciences, National University of Singapore, Singapore, 119228, Singapore.
¹³ School of Biological Sciences, Nanyang Technological University, Singapore, 639798, Singapore.
¹⁴ Department of Pathology, National University Health System, Singapore, 119074, Singapore.
¹⁵ Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore.
¹⁶ Division of Gastroenterology and Hepatology, National University Health System, Singapore, 119074, Singapore.
¹⁷ Department of Hematology and Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.
¹⁸ Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore. [email protected].
¹⁹ Department of Hematology-Oncology, National University Cancer Institute, Singapore, 119074, Singapore. [email protected].
²⁰ Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore. [email protected].

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 MET^N375S to interact with HER2 in a ligand-independent fashion. The resultant MET^N375S/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^N375S. These results establish MET^N375S as a biologically distinct and clinically actionable molecular subset of SCCs that are uniquely amenable to HER2 blocking therapies.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / pharmacology
Antineoplastic Agents / therapeutic use
Carcinoma, Squamous Cell / drug therapy
Carcinoma, Squamous Cell / genetics*
Carcinoma, Squamous Cell / mortality
Carcinoma, Squamous Cell / pathology*
Cell Line, Tumor
Head and Neck Neoplasms / drug therapy
Head and Neck Neoplasms / genetics
Head and Neck Neoplasms / mortality
Head and Neck Neoplasms / pathology
Humans
Lung Neoplasms / drug therapy
Lung Neoplasms / genetics
Lung Neoplasms / mortality
Lung Neoplasms / pathology
Mice
Mutation
Phenotype
Phosphorylation / drug effects
Polymorphism, Genetic
Prognosis
Protein Binding
Protein Interaction Domains and Motifs
Protein Kinase Inhibitors / pharmacology
Protein Kinase Inhibitors / therapeutic use
Proto-Oncogene Proteins c-met / chemistry
Proto-Oncogene Proteins c-met / genetics*
Proto-Oncogene Proteins c-met / metabolism*
Receptor, ErbB-2 / antagonists & inhibitors
Receptor, ErbB-2 / metabolism*
Signal Transduction / drug effects
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
ERBB2 protein, human
MET protein, human
Proto-Oncogene Proteins c-met
Receptor, ErbB-2