Gain-of-function RHOA mutations promote focal adhesion kinase activation and dependency in diffuse gastric cancer

Haisheng Zhang, Antje Schaefer, Yichen Wang, Richard G. Hodge, Devon R. Blake, J. Nathaniel Diehl, Alex G. Papageorge, Matthew D. Stachler, Jennifer Liao, Jin Zhou, Zhong Wu, Fahire G. Akarca, Leonie K. de Klerk, Sarah Derks, Mariaelena Pierobon, Katherine A. Hoadley, Timothy C. Wang, George Church, Kwok Kin Wong, Emanuel F. PetricoinAdrienne D. Cox, Douglas R. Lowy, Channing J. Der, Adam J. Bass*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Diffuse gastric cancer (DGC) is a lethal malignancy lacking effective systemic therapy. Among the most provocative recent results in DGC has been that of highly recurrent missense mutations in the GTPase RHOA. The function of these mutations has remained unresolved. We demonstrate that RHOAY42C, the most common RHOA mutation in DGC, is a gain-of-function oncogenic mutant, and that expression of RHOAY42C with inactivation of the canonical tumor suppressor Cdh1 induces metastatic DGC in a mouse model. Biochemically, RHOAY42C exhibits impaired Y42C GTP hydrolysis and enhances interaction with its effector ROCK. RHOA mutation and Cdh1 loss induce actin/cytoskeletal rearrangements and activity of focal adhesion kinase (FAK), which activates YAP–TAZ, PI3K–AKT, and β-catenin. RHOAY42C murine models were sensitive to FAK inhibition and to combined YAP and PI3K pathway blockade. These results, coupled with sensitivity to FAK inhibition in patient-derived DGC cell lines, nominate FAK as a novel target for these cancers. SIGNIFICANCE: The functional significance of recurrent RHOA mutations in DGC has remained unresolved. Through biochemical studies and mouse modeling of the hotspot RHOAY42C mutation, we establish that these mutations are activating, detail their effects upon cell signaling, and define how RHOA-mediated FAK activation imparts sensitivity to pharmacologic FAK inhibitors.

Original languageEnglish
Pages (from-to)288-305
Number of pages18
JournalCancer discovery
Volume10
Issue number2
DOIs
Publication statusPublished - Feb 2020

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