Medical Genetics Commons^™

A Genome-Wide Screen Identifies Pdpk1 As A Target To Enhance The Efficacy Of Mek1/2 Inhibitors, Weijia Cai, Nicole A. Wilski, Timothy J. Purwin, Megane Vernon, Manoela Tiago, Andrew E. Aplin

Department of Cancer Biology Faculty Papers

Melanomas frequently harbor activating NRAS mutations. However, limited advance has been made in developing targeted therapy options for NRAS mutant melanoma patients. MEK inhibitors (MEKi) show modest efficacy in the clinic and their actions need to be optimized. In this study, we performed a genome-wide CRISPR-Cas9-based screen and demonstrated that loss of Phosphoinositide-dependent kinase-1 (PDPK1) enhances the efficacy of MEKi. The synergistic effects of PDPK1 loss and MEKi was validated in NRAS mutant melanoma cell lines using pharmacological and molecular approaches. Combined PDPK1 inhibitors (PDPK1i) with MEKi suppressed NRAS mutant xenograft growth and induced gasdermin E-associated pyroptosis. In an immune-competent …

Teratology Primer-2nd Edition (7/9/2010), Sura Alwan, Steven B. Bleyl, Robert L. Brent, Christina D. Chambers, George P. Daston, Elaine M. Faustman, Richard H. Finnell, F. Clarke Fraser, Jan M. Freidman, Adriane Fugh-Berman, John M. Graham, Jr., Barbara F. Hales, Deborah K. Hansen, Lewis B. Holmes, Ronald D. Hood, Robert J. Kavlock, Thomas B. Knudsen, Joseph Lary, Donald R. Mattison, Richard K. Miller, James L. Mills, Janine E. Polifka, Sonja A. Rasmussen, Bernard Robaire, John M. Rogers, Gary C. Schoenwolf, Anthony R. Scialli, Gary M. Shaw, Amar V. Singh, William Slikker, Jr., Ann P. Streissguth, Melissa S. Tassinari, Janet Uriu-Adams, Charles V. Vorhees, Elora J. Weringer

Department of Pediatrics Faculty Papers

Foreword:

What is Teratology?

“What a piece of work is an embryo!” as Hamlet might have said. “In form and moving how express and admirable! In complexity how infinite!” It starts as a single cell, which by repeated divisions gives rise to many genetically identical cells. These cells receive signals from their surroundings and from one another as to where they are in this ball of cells —front or back, right or left, headwards or tailwards, and what they are destined to become. Each cell commits itself to being one of many types; the cells migrate, combine into tissues, or …