Gain-of-Function RHOA Mutations Promote Focal Adhesion Kinase Activation and Dependency in Diffuse Gastric Cancer
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 GTP hydrolysis and enhances interaction with its effector ROCK. RHOAY42C 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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Feb 01, 2020
- Source ID
- 10.1158/2159-8290.cd-19-0811
Entities
People
- Adam J. Bass
- Adrienne D Cox
- Alex G. Papageorge
- Antje Schaefer
- Channing Der
- Devon R Blake
- Douglas R. Lowy
- Emanuel F. Petricoin
- Fahire G Akarca
- George M. Church
- Haisheng Zhang
- J. Nathaniel Diehl
- Jennifer Liao
- Jin Zhou
- Katherine A. Hoadley
- Kwok-kin Wong
- Leonie K de Klerk
- Mariaelena Pierobon
- Matthew D. Stachler
- Richard G Hodge
- Sarah Derks
- Timothy C Wang
- Zhong Wu
Organizations
- Columbia University
- Debbie's Dream Foundation
- George Mason University
- Harvard Medical School
- Massachusetts Institute of Technology
- National Cancer Institute
- National Institutes of Health
- New York University
- Southern Medical University
- University of North Carolina at Chapel Hill