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Cancer Discov DOI:10.1158/2159-8290.CD-19-0811

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

Publication TypeJournal Article
Year of Publication2020
AuthorsZhang, H, Schaefer, A, Wang, Y, Hodge, RG, Blake, DR, J Diehl, N, Papageorge, AG, Stachler, MD, Liao, J, Zhou, J, Wu, Z, Akarca, FG, de Klerk, LK, Derks, S, Pierobon, M, Hoadley, KA, Wang, TC, Church, G, Wong, K-K, Petricoin, EF, Cox, AD, Lowy, DR, Der, CJ, Bass, AJ
JournalCancer Discov
Date Published2020 Feb

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 RHOA, the most common RHOA mutation in DGC, is a gain-of-function oncogenic mutant, and that expression of RHOA with inactivation of the canonical tumor suppressor induces metastatic DGC in a mouse model. Biochemically, RHOA exhibits impaired GTP hydrolysis and enhances interaction with its effector ROCK. mutation and loss induce actin/cytoskeletal rearrangements and activity of focal adhesion kinase (FAK), which activates YAP-TAZ, PI3K-AKT, and β-catenin. RHOA 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 RHOA 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...


Alternate JournalCancer Discov
PubMed ID31771969
PubMed Central IDPMC7007383
Grant ListP30 ES010126 / ES / NIEHS NIH HHS / United States
P30 DK034854 / DK / NIDDK NIH HHS / United States
F31 CA216965 / CA / NCI NIH HHS / United States
T32 CA071341 / CA / NCI NIH HHS / United States
R01 CA224428 / CA / NCI NIH HHS / United States