Abstract 2301: Targeting the MUVB complex or downstream G2/M proteins potentiates CDK4/6 inhibitor efficacy in breast cancer

Abstract

Uncontrolled progression through the cell cycle sustains the growth and progression of cancer. The cell cycle is comprised of 4 phases that are tightly regulated by two key transcriptional modulators, RB-E2F and MUVB complexes that regulate gene expression during the G1/S and G2/M cell cycle transitions, respectively. Target transcriptomes of both complexes overlap, suggesting that maximal inhibition of cell cycle progression, requires targeting both. Inhibitors that regulate the RB-E2F signaling axis have been FDA approved for treatment of a subset of breast cancers. These drugs specifically inhibit two kinases involved in the cell cycle known as CDK4 and CDK6. Palbociclib and abemaciclib, CDK4/CDK6 inhibitors (CDK4/6i), decrease cell proliferation by inducing a G1 cell cycle arrest. In contrast to CDK4/6, we previously reported that the activity of MUVB complex can be repressed using inhibitors of BET proteins, including the tool compound, JQ1. We hypothesized that dual targeting of MUVB and CDK4/CDK6 will synergize in breast cancer models to further decrease growth. To test this hypothesis, we assessed the impact of growth by adding JQ-1 to CDK4/6i in multiple intrinsically resistant cell lines. We found that addition of JQ-1 reduced IC50 of CDK4/6i by 60-75% and that the combination displayed synergistic growth suppression. Mechanistically, analysis of mRNA and protein expression revealed that the combination had greater ability to suppress expression of proteins that are MUVB target genes, G2/M, compared to single agents. We found through genetic and pharmacological approaches that inhibition of G2/M proteins Aurora Kinase A and NEK2 mediated CDK4/6i inhibitor response. Preclinical xenograft models confirmed that combined inhibition of CDK4/6 and MUVB, NEK2, or Aurora Kinase A can synergistically suppress tumor growth. Together, these results indicate that dual targeting of distinct phases of the cell cycle should be a more efficacious approach for suppressing breast cancer growth and provide a potential approach for blocking the acquisition of resistance to CDK4/6 inhibitors, a major clinical challenge for the treatment of luminal breast cancer. Citation Format: Leslie Cuellar-Vite, Kristen Weber-Bonk, Ruth A. Keri. Targeting the MUVB complex or downstream G2/M proteins potentiates CDK4/6 inhibitor efficacy in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2301.