Abstract 1805: RAB10, a new target to tackle SMAD4 deficient cancers

Abstract

Abstract TGFb pathway is an important signaling process that regulates the homeostasis of epithelial, stromal or immune cells. Misregulations of this pathway contribute to different pathologies such as cancer, fibrosis, nash or inflammatory diseases. SMAD4 genetic alterations, either via genomic loss or via mutations, can be found in many cancer types. SMAD4 is mutated or deleted in 10-15% of colorectal cancers and in 20-50% of pancreatic cancer. The poorer prognosis of colorectal cancers and pancreatic cancers patients harboring SMAD4 alterations makes SMAD4 deficiency interesting to harness for therapy. Anticancer opportunity created by loss of SMAD4 function/protein could be addressed by identifying synthetic lethal genes that encode for druggable proteins. CRISPR/CAS9 is a revolutionary discovery to produce gene knockout. CRISPR/CAS9 viability screen is a tool of choice to pinpoint new synthetic lethality interactions. In this work, to extend the genetic vulnerabilities of SMAD4-deficient tumors, we conducted a pooled genome-wide loss of function CRISPR/Cas9 screen in sets of 4 non-isogenic colorectal and pancreatic cancers cancer cell lines harboring wild-type and mutant SMAD4. We identified known and novel genetic alterations that make SMAD4-altered colorectal cancers & pancreatic cancers cells vulnerable. We will present the validation of the Ras-related protein Rab-10 (RAB10) as synthetic lethal gene with SMAD4 alteration. Citation Format: Christophe Marcireau, Hélène Erasimus, Vanessa Kolnik, Frederic Lacroix, Stephane D’agostino, Olivier Lemaitre, Alexandre Rohaut, Isabelle sanchez, Sukhvinder Sidhu, Gilbert Thill, Laurent Debussche, Michel Didier. RAB10, a new target to tackle SMAD4 deficient cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1805.