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 RHOA Y42C , the most common RHOA mutation in DGC, is a gain-offunction oncogenic mutant, and that expression of RHOA Y42C with inactivation of the canonical tumor suppressor Cdh1 induces metastatic DGC in a mouse model. Biochemically, RHOA Y42C 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. RHOA Y42C 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 signifi cance of recurrent RHOA mutations in DGC has remained unresolved. Through biochemical studies and mouse modeling of the hotspot RHOA Y42C mutation, we establish that these mutations are activating, detail their effects upon cell signaling, and defi ne how RHOA-mediated FAK activation imparts sensitivity to pharmacologic FAK inhibitors.

MST4 kinase suppresses gastric tumorigenesis by limiting YAP activation via a non-canonical pathway

“…Given the strong positive correlation of YAP hyperactivation with poor prognosis of GC, growing efforts are being made to target the Hippo–YAP pathway for treating GC (Calses et al, 2019; Huang et al, 2020; Jiao et al, 2014, 2018; Kang et al, 2011; Tang et al, 2019a; Zanconato et al, 2016; Zhang et al, 2020). We previously observed that YAP was up-regulated in GC, and such up-regulation was positively correlated with tumor stages (Jiao et al, 2014, 2018).…”

“…However, it is rare or less common to observe mutation or abnormal expression of the upstream tumor suppressor kinases (Zheng and Pan, 2019). For example, we and others have shown that YAP is hyperactivated in GC (Jiao et al, 2014; Kang et al, 2011; Zhang et al, 2020) and that constitutive activation of YAP drives GC development (Choi et al, 2018; Huang et al, 2020; Jiao et al, 2018); yet MST1/2 and LATS2 kinases seem to be normally expressed without any mutation in GC. These phenomena hint at the possibility of additional or alternative regulation of YAP activity beyond the canonical Hippo kinase cascade.…”

A ceRNA network and a potential regulatory axis in gastric cancer with different degrees of immune cell infiltration

“…Gastric cancer has a high mortality rate, and threatens human life and health 33 . The extremely poor prognosis of patients with gastric cancer greatly promotes the development of an effective treatment measure 34 .…”

Hormones Secretion and Rho GTPases in Neuroendocrine Tumors

“…P29S-Rac1 is a fast cycling mutant with spontaneous activation and therefore acts as a gain-of-function mutation [26,27]. The Y42C mutation reduces both intrinsic-and GAP-stimulated GTP hydrolysis of RhoA, thereby enhancing the active GTP-bound form [28]. On the contrary, Wang et al proposed that the Y42C mutation decreased the level of the activated GTP-associated form of RhoA [29].…”