Abstract LB203: CRISPR anchor screens to identify co-vulnerabilities and drug combinations in DepMap

Abstract The Cancer Dependency Map (DepMap) aims to systematically map the landscape of cancer vulnerabilities by profiling a wide range of cancer cell lines that collectively represent the heterogeneity of human cancer. An increasing number of targets and biomarkers emerging from this effort are in drug development or clinical trials. However, it is clear that drug resistance is a significant challenge and that drug combinations will be required. CRISPR anchor screens involve introducing an "anchor" which can be either a drug or genetic perturbation, alongside the sgRNA library. This approach provides a way to investigate resistance mechanisms, potential drug combinations, or co-vulnerabilities. As a proof of concept, here we describe CRISPR anchor screens with MRTX1133 as the anchor, which is a potent and selective KRASG12D inhibitor currently in clinical trials. We performed genome-scale loss-of-function CRISPR-Cas12a screens in the presence of MRTX1133 in pancreatic and lung cancer cell lines that harbor the KRASG12D. The goal of these screens was to identify cancer dependencies that are either present or enhanced in the presence of MRTX1133. We find multiple such MRTX1133-induced dependencies that are either common across all cell lines screened or unique to one or a few. This shows that the response to MRTX1133 can vary depending on the context, highlighting the importance of finding biomarkers to predict the response. Identifying the biomarkers of these context-specific dependencies would provide strategies to select patient populations that would respond to the drug combinations. This study not only provides valuable insights into enhancing the efficacy of KRAS-targeted therapies but also serves as a pioneering effort in incorporating innovative CRISPR screen modalities into the DepMap. Citation Format: Jenny Serra-Vinardell, Zoe Posner, Alison Cameron, Yuqi Chen, Negin Karisani, Barbara De Kegel, Joshua M. Dempster, Andrew J. Aguirre, Francisca Vazquez. CRISPR anchor screens to identify co-vulnerabilities and drug combinations in DepMap abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (7Suppl): Abstract nr LB203.