Dysregulation of the Hippo signaling pathway and the consequent YAP1 activation is a frequent event in human malignancies, yet the underlying molecular mechanisms are still poorly understood. A pancancer analysis of core Hippo kinases and their candidate regulating molecules revealed few alterations in the canonical Hippo pathway, but very frequent genetic alterations in the FAT family of atypical cadherins. By focusing on head and neck squamous cell carcinoma (HNSCC), which displays frequent FAT1 alterations (29.8%), we provide evidence that FAT1 functional loss results in YAP1 activation. Mechanistically, we found that FAT1 assembles a multimeric Hippo signaling complex (signalome), resulting in activation of core Hippo kinases by TAOKs and consequent YAP1 inactivation. We also show that unrestrained YAP1 acts as an oncogenic driver in HNSCC, and that targeting YAP1 may represent an attractive precision therapeutic option for cancers harboring genomic alterations in the FAT1 tumor suppressor genes.

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G protein coupled receptors (GPCRs) represent the largest class of drug target among currently approved small molecules. However, there is a dearth of oncology drugs targeting GPCRs. Analysis of cancer genomes reveals that G proteins often harbor activating mutations, inherently making their cognate receptor resistant to modulation. In particular, activated GNAS mutants, encoding a constitutively active, GTPase defective Gαs, can be identified in approximately 5% of all sequenced tumors, including 4% of colorectal cancers (CRCs). By stimulating adenylyl cyclases, GNAS activation leads to the intracellular accumulation of cAMP, a central second messenger, which in turn, activates protein kinase A (PKA). Similarly, 10% of CRC patients harbor gene amplification of GNAS, and another 45% have genetic alterations in PKA subunits, adenylyl cyclases, or phosphodiesterases (which inhibit cAMP accumulation). These findings highlight the importance of understanding oncogenic signaling downstream of GPCRs and the potential role of GNAS‐PKA signaling in CRC. The aim of our study is to define the contribution of the GNAS‐PKA pathway in CRCs and explore the cancer‐associated GNAS‐PKA signaling network. We hypothesize that increased PKA activity downstream of GNAS mutations, or in response to persistent GPCR activation, plays a central role in the growth and progression of CRCs. Preliminary results demonstrate that PKA inhibition significantly reduces tumor burden in xenograft mouse models. Interestingly, activation of GNAS alone in both transgenic and chemical carcinogen mouse models is insufficient to induce tumorigenesis. However, upon the co‐activation of GNAS and RAS, mice show rapid development of squamous cell carcinoma. This finding is strongly supported by bioinformatic analysis revealing a co‐occurrence of GNAS and KRAS mutations clinically. We are currently profiling the GNAS‐PKA pathway by large scale transcriptomic and proteomic experiments to understand signaling circuitries and mechanisms of tumorigenesis. Emerging results from our studies will be presented.Support or Funding InformationDana Steffen was supported by the National Science Foundation Graduate Research Fellowship Program (NSF GRFP) and the UCSD Graduate Training Program in Cellular and Molecular Pharmacology through an institutional training grant from the National Institute of General Medical Sciences (T32 GM007752). This study is supported in part by the San Diego NCI Cancer Centers Council (C3) Collaborative Translational Cancer Research Pilot Grant.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.