GNAS‐PKA Oncosignaling Network in Colorectal Cancer

Abstract

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.

Targeted variant prevalence of FBXW7 gene mutation in colorectal carcinoma propagation. The first systematic review and meta-analysis

“…Similar to the APC, BRAF, and KRAS genes, the FBXW7 gene aberrations are commonly identified in many cancer types, identified in about 5–10 % of all sequenced cancer cases [ [13] , [14] , [15] , [16] ], approximately 5–7% in CRCs [ 17 ], 30 % in cholangiocarcinoma [ 13 ], and 15 % in hepatic cancer [ 18 , 19 ]. An important pitfall hindering cancer-sequencing exploration is the limited headway to substantively detect variant genes with reduced recurrence mutation rate “i.e.…”

A GNAS Gene Mutation’s Independent Expression in the Growth of Colorectal Cancer: A Systematic Review and Meta-Analysis

“…Worldwide, colorectal cancer (CRC) is a foremost contributor to cancer-related death annually and continues to pose a significant challenge to the world [ 1 ]. With reports of greater than 1.8 million new cases of CRC diagnoses and approximately 0.86 million deaths throughout the globe in 2018 [ 2 ], CRC is the third most frequently occurring cancer, and the third most common cause of cancer-associated deaths in both genders [ 3 ], representing 10% of all cancer diagnosed yearly [ 4 ]. Over the past decade, increasing evidence points to the role of G-protein activating subunit gene mutations in the development of tumours, i.e., CRC [ 5 ].…”

“…Just as with the KRAS, the GNAS gene mutations are frequently detected in lots of tumour types, detected in about 5% of all sequenced malignant tumours, as well as 4–7% in colorectal cancers (CRCs) [ 4 ], 41% in intraductal papillary neoplasms of the pancreas [ 7 ] and about 15% in liver cancer [ 8 ]. GNAS gene mutations has been altered in 3.21% of all cancers [ 1 ].…”