Abstract PR04: Integration of CRISPR-Cas9, RNAi and pharmacologic screens identify actionable targets in a rare cancer

Abstract

Abstract Loss-of-function screening using RNAi technologies over the past decade and more recently with CRISPR-Cas9 technologies have been applied to well-established cancer models. We asked if minimally passaged cancer models would tolerate such screening modalities, particularly perturbations focused on actionable drug targets. We have established a patient derived model, CLF-PED-015-T, as a proof of concept to test this question. After validating that the cell line retains the major genomic, transcriptomic and tumorigenic properties of the tissue it was derived from, we then performed systematic genetic screens using both CRISPR-Cas9 and RNAi to identify potentially actionable vulnerabilities. We then overlapped this with pharmacologic screens. We identified dependencies to CDK4 and XPO1 that spanned all three screens. These dependencies have subsequently validated in an in vivo model. These results suggest use of such technologies at early stages of patient derived model development is feasible. This abstract is also being presented as Poster B14. Citation Format: Andrew L. Hong, Yuen-Yi Tseng, Glenn Cowley, Oliver Jonas, Jaime Cheah, Mihir Doshi, Bryan Kynnap, Coyin Oy, Paula Keskula, Gregory Kryukov, Michael Cima, Robert Langer, Stuart Schreiber, David Root, Jesse Boehm, William Hahn. Integration of CRISPR-Cas9, RNAi and pharmacologic screens identify actionable targets in a rare cancer. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr PR04.