Abstract
Abstract CRISPR/Cas9 functional genetic screens are a powerful tool to discover drug targets in cancer. While many screens have been performed for identification of intrinsic cancer vulnerabilities, synthetic lethalities of targeted therapies remain largely unexplored, despite the fact that they may provide a potential targets and pathways for potential combination therapies, advance understanding of target biology, and hone patient selection strategies. To discover novel combination targets of Palbociclib, a CDK2 inhibitor, and a CDK2,4,6 inhibitor, we have screened a genome-wide CRISPR library in priority tumors with genetic background of interest, including ER+ breast cancer (HCC1428, MCF7), cyclin E amplified breast (HCC1806) and/or ovarian cancer (OVCAR4), and pancreatic cancer cell lines (MIAPACA2, Hs766T, SU8686). We analyzed the samples by condition and compared using MAGeCK-MLE for gene-level drop out and enrichment to identify common sensitizers and resistors to different CDK inhibitors. Differential genes, complexes, and pathways were assessed, and we have found that genes involved in G1/S transition (CyclinE/CDK2) are top Palbo sensitizers and CDK1/CyclinA, CDC25A/B, MuvB complex (MYBL2 and FOXM1) are major CDK2 sensitizing genes. In addition to sensitizers, we have identified genes with strong signals of resistance to CDK inhibitors. Furthermore, we highlighted major mechanisms influencing response to CDK2 inhibitors; 1) Regulation of DREAM may influence response to CDK inhibitors, 2) Regulation of cell cycle check points mediated by CDC25. Our targeted CRISPR KO screens in different CDKi combinations have identified common sensitizers and mediators of resistance to CDK inhibitors, and highlighted biology worthy of deeper consideration and offers opportunities to consider new directions for therapeutic intervention into the cancer cell cycle Citation Format: Kimberly H Kim, Jonathan Almaden, vinu arunachalam, Todd VanArsdale, chaoting liu. Discovery of combination targets of CDK inhibitors from CRISPR screens [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr LBA011.
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