While mutational activation of KRAS occurs in nearly all pancreatic ductal adenocarcinomas (PDAC), clinically relevant agents directly targeting KRAS remain elusive. The second most frequent aberration in PDAC is loss of the tumor suppressor CDKN2A, which encodes INK4A, an endogenous inhibitor of the CDK4 and CDK6 cell cycle regulatory proteins that promote G1 cell cycle progression. KRAS and INK4A mutations cooperate to accelerate PDAC metastatic development, in part, by converging to block RB tumor suppressor activity. While no anti-KRAS targeted therapies have reached the clinic, pharmacologic restoration of CDKN2A function by inhibition of CDK4/6 may be an effective anti-KRAS therapeutic strategy. We found that CDK4/6 inhibitors (e.g., palbociclib) elicited single-agent activity in a subset of tested PDAC cell lines. Furthermore, concurrent treatment with the ERK inhibitor SCH772984 caused a potent synergistic reduction in anchorage-dependent and -independent cell growth, induced apoptosis, and increased senescence and G1 arrest. We next sought to identify novel genes that regulate sensitivity to palbociclib. Using a CRISPR/Cas9 loss-of-function screen, we individually silenced expression of 2500 genes from the “druggable genome” in combination with palbociclib. We identified genes that caused synergistic growth suppression in combination, suggesting small molecule combinations to overcome de novo or acquired CDK4/6 inhibitor resistance in the clinic. We also identified genes whose loss imparts a survival advantage, suggesting possible resistance mechanisms to single-agent CDK4/6 inhibition. In total, these data suggest that CDK4/6 inhibitors alone, or in combination, may benefit patients clinically.

Citation Format: Craig Goodwin, Sehrish Javaid, Adrienne D. Cox, Kris Wood, Channing Der. Application of a CRISPR/Cas9 screen to identify novel therapeutic strategies with CDK4/6 inhibitors in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-276.