Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Anna L. Guarnieri
Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Molishree Joshi
Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Functional Genomics Facility, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Huy N. Duc
Functional Genomics Facility, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Madison C. Laird
Functional Genomics Facility, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Ahwan Pandey
Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia
Santosh Khanal
Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Emily Dohm
Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Aimee K. Bui
Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Kelly D. Sullivan
Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Pediatrics, Section of Developmental Biology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Matthew D. Galbraith
Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Zdenek Andrysik
Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Corresponding author
Joaquin M. Espinosa
Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Functional Genomics Facility, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Corresponding author
Summary: Inactivation of the p53 tumor suppressor, either by mutations or through hyperactivation of repressors such as MDM2 and MDM4, is a hallmark of cancer. Although many inhibitors of the p53-MDM2/4 interaction have been developed, such as Nutlin, their therapeutic value is limited by highly heterogeneous cellular responses. We report here a multi-omics investigation of the cellular response to MDM2/4 inhibitors, leading to identification of FAM193A as a widespread regulator of p53 function. CRISPR screening identified FAM193A as necessary for the response to Nutlin. FAM193A expression correlates with Nutlin sensitivity across hundreds of cell lines. Furthermore, genetic codependency data highlight FAM193A as a component of the p53 pathway across diverse tumor types. Mechanistically, FAM193A interacts with MDM4, and FAM193A depletion stabilizes MDM4 and inhibits the p53 transcriptional program. Last, FAM193A expression is associated with better prognosis in multiple malignancies. Altogether, these results identify FAM193A as a positive regulator of p53.
