2. Academic Validation
  3. A Platform of Synthetic Lethal Gene Interaction Networks Reveals that the GNAQ Uveal Melanoma Oncogene Controls the Hippo Pathway through FAK

A Platform of Synthetic Lethal Gene Interaction Networks Reveals that the GNAQ Uveal Melanoma Oncogene Controls the Hippo Pathway through FAK

  • Cancer Cell. 2019 Mar 18;35(3):457-472.e5. doi: 10.1016/j.ccell.2019.01.009.
Xiaodong Feng 1,  Nadia Arang 2,  Damiano Cosimo Rigiracciolo 3,  Joo Sang Lee 4,  Huwate Yeerna 5,  Zhiyong Wang 2,  Simone Lubrano 5,  Ayush Kishore 5,  Jonathan A Pachter 6,  Gabriele M König 7,  Marcello Maggiolini 8,  Evi Kostenis 7,  David D Schlaepfer 5,  Pablo Tamayo 9,  Qianming Chen 10,  Eytan Ruppin 11,  J Silvio Gutkind 12
Affiliations

Affiliations

  • 1 Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA; State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China.
  • 2 Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA; Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA 92093, USA.
  • 3 Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA; Department of Pharmacy and Health and Nutritional Sciences, University of Calabria, Rende 87036, Italy.
  • 4 Cancer Data Science Laboratory, National Cancer Institute, National Institute of Health, Bethesda, MD 20892, USA; Center for Bioinformatics and Computational Biology & Department of Computer Sciences, University of Maryland, College Park, MD 20742, USA. Electronic address: lee.joosang@gmail.com.
  • 5 Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
  • 6 Verastem Oncology, Needham, MA, USA.
  • 7 Molecular, Cellular and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn, Bonn 53115, Germany.
  • 8 Department of Pharmacy and Health and Nutritional Sciences, University of Calabria, Rende 87036, Italy.
  • 9 Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA; Division of Medical Genetics, UC San Diego School of Medicine, La Jolla, CA 92093, USA.
  • 10 State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China. Electronic address: qmchen@scu.edu.cn.
  • 11 Cancer Data Science Laboratory, National Cancer Institute, National Institute of Health, Bethesda, MD 20892, USA; Center for Bioinformatics and Computational Biology & Department of Computer Sciences, University of Maryland, College Park, MD 20742, USA. Electronic address: eyruppin@gmail.com.
  • 12 Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: sgutkind@ucsd.edu.
PMID: 30773340 DOI: 10.1016/j.ccell.2019.01.009
Abstract

Activating mutations in GNAQ/GNA11, encoding Gαq G proteins, are initiating oncogenic events in uveal melanoma (UM). However, there are no effective therapies for UM. Using an integrated bioinformatics pipeline, we found that PTK2, encoding focal adhesion kinase (FAK), represents a candidate synthetic lethal gene with GNAQ activation. We show that Gαq activates FAK through TRIO-RhoA non-canonical Gαq-signaling, and genetic ablation or pharmacological inhibition of FAK inhibits UM growth. Analysis of the FAK-regulated transcriptome demonstrated that GNAQ stimulates YAP through FAK. Dissection of the underlying mechanism revealed that FAK regulates YAP by tyrosine phosphorylation of MOB1, inhibiting core Hippo signaling. Our findings establish FAK as a potential therapeutic target for UM and other Gαq-driven pathophysiologies that involve unrestrained YAP function.

Keywords

FAK; G protein; GNA11; GNAQ; Hippo; MOB1; PTK2; YAP; signal transduction; uveal melanoma.

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