Abstract B024: Phosphoinositide focused CRISPR screen reveals ITGAV as a critical gene in pancreatic cancer growth and invasion

Abstract

Abstract Background: Pancreatic Cancer (PC) is one of the most aggressive cancer types, with less than 10% of patients surviving at 5-years. One hallmark of PC is the frequent mutation of the oncogene KRAS resulting in the constitutive activation of the phosphoinositide-3-kinase (PI3K) signaling pathway. The PI3K pathway is an intracellular signaling pathway that regulates cell growth, metabolism, and survival in response to extracellular signals. Given the importance of deregulated phosphoinositide (PI) signaling in PC, we hypothesize that genes coding for PI-metabolizing enzymes and effectors may have significant and unappreciated roles in PC. Methods: We generated a CRISPR knockout (KO) library that targets 1,534 PI-associated genes to discover novel essential genes in PC. Results: In a PANC-1 screen, we identified 106 essential genes across all timepoints, including 28 novel candidate genes and 78 previously identified essential genes. Among six validated candidate genes, we demonstrate that Integrin Subunit Alpha V (ITGAV) is a protein with clinical importance in PC. Treatment of PC cell lines with an ITGAV integrin antagonist as well as KO of ITGAV resulted in reduced cancer associated phenotypes in vitro, including reduced proliferation rate and compromised migration and invasion capacity. Ongoing studies will investigate perturbations in signaling pathways associated with ITGAV, and aim to elucidate roles for ITGAV in metastatic progression and therapy response. Conclusions: Overall, these findings indicate that ITGAV inhibition represents a putative strategy for the treatment of PC. Citation Format: Daniel K.C. Lee, Ryan Loke, Lydia To, Keyue Chen, Jonathan T.S. Chow, Leonardo Salmena. Phosphoinositide focused CRISPR screen reveals ITGAV as a critical gene in pancreatic cancer growth and invasion [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B024.