Abstract PR06: Combinations with CDK4/6 inhibitors to treat cancers with mutations in both KRAS and CDKN2A

Oncogenic KRAS mutations commonly co-occur with loss of CDKN2A in pancreas and lung cancer. Both mutations are known to activate D-cyclin dependent kinases and therefore may confer sensitivity to drugs that inhibit CDK4 and CDK6 (CDK4/6i). Indeed, preclinical studies have shown that KRAS/CDKN2A double-mutant cancers are reasonably sensitive to CDK4/6 inhibitors and the CDK4/6i abemaciclib showed evidence of benefit in clinical studies of KRAS-mutant NSCLC (1) (http://www.ascopost.com/News/58135). However, despite the encouraging result, abemaciclib did not meet a prespecified overall survival endpoint in the JUNIPER trial, and it has been shown that failure to suppress CDK2 activity diminishes the antiproliferative activity of CDK4/6i in KRAS/CDKN2A mutant cancer cells (2). Since CDK2-specific inhibitors are not available for clinical combination strategies, it is unclear how to exploit this discovery. We employed CRISPR and shRNA genome-wide library screens to identify alternate mechanisms to potentiate the CDK4/6 inhibitor abemaciclib in this class of cancer. Depletion of Src family or Ras-MAPK pathway genes emerged as consistent hits in both lung and pancreas cancer cells with KRAS/CDKN2A mutations. Inhibitors of Src family or Ras-MAPK pathway kinases led to a strong suppression of CDK2 activity and apoptosis when combined with abemaciclib. Across a panel of cancer cell lines, ERKi LY3214996 combined with abemaciclib potently inhibited the growth of KRAS/CDKN2A mutant cancer cells. The combination of LY3214996 with abemaciclib was well tolerated in vivo and caused regressions in mice bearing human KRAS/CDKN2A mutant tumor xenografts, supporting the clinical examination of this drug combination. References 1. Patnaik A et al. Efficacy and safety of abemaciclib, an inhibitor of CDK4 and CDK6, for patients with breast cancer, non-small cell lung cancer, and other solid tumors. Cancer Discov 2016;6:740-53. 2. Gong X et al. Genomic aberrations that activate D-type cyclins are associated with enhanced sensitivity to the CDK4 and CDK6 inhibitor abemaciclib. Cancer Cell 2017;32:761-76 e766. This abstract is also being presented as Poster A33. Citation Format: Lacey Litchfield, Avnish Kapoor, Wenjuan Wu, Xueqian Gong, Yue Webster, Sheng-Bin Peng, Shripad Bhagwat, Farhana Merzoug, Sean G. Buchanan. Combinations with CDK4/6 inhibitors to treat cancers with mutations in both KRAS and CDKN2A [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr PR06.