Format

Send to

Choose Destination
Cancer Discov. 2020 Feb;10(2):288-305. doi: 10.1158/2159-8290.CD-19-0811. Epub 2019 Nov 26.

Gain-of-Function RHOA Mutations Promote Focal Adhesion Kinase Activation and Dependency in Diffuse Gastric Cancer.

Author information

1
Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.
2
Division of Molecular and Cellular Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
3
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
4
Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
5
Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
6
Laboratory of Cellular Oncology, NCI, NIH, Bethesda, Maryland.
7
Center for Applied Proteomics and Molecular Medicine, School of Systems Biology, George Mason University, Manassas, Virginia.
8
Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
9
Division of Gastroenterology, Columbia University Medical Center, New York, New York.
10
Harvard, MIT, Blavatnik Institute, Wyss Institute, Boston, Massachusetts.
11
Division of Hematology and Oncology, New York University, New York, New York.
12
Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
13
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. adam_bass@dfci.harvard.edu channing_der@med.unc.edu.
14
Division of Molecular and Cellular Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. adam_bass@dfci.harvard.edu channing_der@med.unc.edu.
15
Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
#
Contributed equally

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. RHOA Y42C 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.See related commentary by Benton and Chernoff, p. 182.This article is highlighted in the In This Issue feature, p. 161.

Comment in

PMID:
31771969
PMCID:
PMC7007383
[Available on 2020-08-01]
DOI:
10.1158/2159-8290.CD-19-0811

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center