J. Silvio Gutkind, Ph.D.
Distinguished Professor & Chair of Pharmacology
J.Silvio Gutkind, Ph.D.
Distinguished Professor & Chair of Pharmacology
Research Interests
The goal of our research program is to exploit the emerging information on dysregulated signaling circuitries and individual genomic and molecular alterations to identify new therapeutic options to prevent and treat cancer. Our laboratory has focused on the study of the oncogenic activity of G proteins and G protein coupled receptors (GPCRs), including virallyencoded GPCRs, to dissect the signaling pathways regulating normal and aberrant cell growth, tumor-induced angiogenesis, and metastasis. We are now investigating the mechanisms by which genetic mutations in Gαq proteins initiate uveal and cutaneous melanoma, the role of Gαs and its target, PKA, in cancer, and how mutations and autocrine activation of GPCRs contribute to tumor progression, immune evasion, and therapy resistance. In parallel, we are exploring the role of the mTOR pathway in cancers of the oral cavity, a disease that results in 250,000 deaths each year worldwide. Based on our prior studies, and emerging results from our recently completed multi-institutional clinical trial targeting mTOR in oral cancer, we are now investigating the effectiveness and mechanism of action of PI3K/mTOR inhibitors for oral cancer prevention and treatment, as single agents and as part of novel multimodal immunotherapies.
Selected Publications
Wu VH, Yung BS, Faraji F, Saddawi-Konefka R, Wang Z, Wenzel AT, Song MJ, Pagadala MS, Clubb LM, Chiou J, Sinha S, Matic M, Raimondi F, Hoang TS, Berdeaux R, Vignali DAA, Iglesias-Bartolome R, Carter H, Ruppin E, Mesirov JP, Gutkind JS. The GPCR-Gαs-PKA signaling axis promotes T cell dysfunction and cancer immunotherapy failure. Nat Immunol. 2023 Aug;24(8):1318-1330. doi: 10.1038/s41590-023-01529-7. Epub 2023 Jun 12. PMID: 37308665.
Saddawi-Konefka R, O'Farrell A, Faraji F, Clubb L, Allevato MM, Jensen SM, Yung BS, Wang Z, Wu VH, Anang NA, Msari RA, Schokrpur S, Pietryga IF, Molinolo AA, Mesirov JP, Simon AB, Fox BA, Bui JD, Sharabi A, Cohen EEW, Califano JA, Gutkind JS. Lymphatic-preserving treatment sequencing with immune checkpoint inhibition unleashes cDC1-dependent antitumor immunity in HNSCC. Nat Commun. 2022 Jul 25;13(1):4298. doi: 10.1038/s41467-022-31941-w. PMID: 35879302; PMCID: PMC9314425.
Wang Z, Goto Y, Allevato MM, Wu VH, Saddawi-Konefka R, Gilardi M, Alvarado D, Yung BS, O'Farrell A, Molinolo AA, Duvvuri U, Grandis JR, Califano JA, Cohen EEW, Gutkind JS. Disruption of the HER3-PI3K-mTOR oncogenic signaling axis and PD-1 blockade as a multimodal precision immunotherapy in head and neck cancer. Nat Commun. 2021;12(1):2383. PMID: 33888713.
Feng X, Arang N, Rigiracciolo DC, Lee JS, Yeerna H, Wang Z, Lubrano S, Kishore A, Pachter JA, König GM, Maggiolini M, Kostenis E, Schlaepfer DD, Tamayo P, Chen Q, Ruppin E, Gutkind JS. A Platform of Synthetic Lethal Gene Interaction Networks Reveals that the GNAQ Uveal Melanoma Oncogene Controls the Hippo Pathway through FAK. Cancer Cell. 2019; 35(3): 457-472. PMID: 30773340.
Feng X, Degese MS, Iglesias-Bartolome R, Vaque JP, Molinolo AA, Rodrigues M, Zaidi MR, Ksander BR, Merlino G, Sodhi A, Chen Q, Gutkind JS. Hippo-independent activation of YAP by the GNAQ uveal melanoma oncogene through a Trio-regulated Rho GTPase signaling circuitry. Cancer Cell. 2014; 25(6):831-45. PMID: 24882515.
O’Hayre M, Vázquez-Prado J, Kufareva I, Stawiski EW, Handel TM, Seshagiri S, Gutkind JS. The emerging mutational landscape of G proteins and G-protein-coupled receptors in cancer. Nat Rev Cancer. 2013; 13(6):412-24. PMID: 23640210
Castellone MD, Teramoto H, Williams BO, Druey KM, Gutkind JS. Prostaglandin E2 promotes colon cancer cell growth through a novel Gs-axin-β-catenin signaling axis. Science. 2005;310(5753):1504-10. PMID: 16293724
Coso OA, Chiariello M, Yu JC, Teramoto H, Crespo P, Xu N, Miki T, Gutkind JS. The small GTP-binding proteins Rac1 and Cdc42 regulate the activity of the JNK/SAPK signaling pathway. Cell. 1995; 81(7):1137-46. PMID: 7600581
Crespo P, Xu N, Simonds WF, Gutkind JS. Ras-dependent activation of MAP kinase pathway mediated by G-protein beta gamma subunits. Nature. 1994;369(6479):418-20. PMID: 8196770