Abstract P3-10-01: Deciphering the heterogeneity of cell cycle in breast cancer and relevance to clinical application of CDK inhibitors

Abstract BACKGROUND: Deregulation of cellular proliferation represents a defining hallmark of cancer. The mechanisms driving aberrant cell cycle progression across different breast cancer subtypes is highly diverse and likely contributes to therapeutic resistance in a variety of contexts. The significance of cell cycle heterogeneity is most clear in the context of metastatic HR+/HER2- breast cancer, wherein acquired and intrinsic resistance to CDK4/6 inhibition represents a significant clinical challenge. However, aberrant cell cycle regulatory networks likely further confound the use of targeted therapies in the context of TNBC. METHODS AND RESULTS: We employed unbiased analyses of large number of breast cancer models to decipher the genetic requirements for different CDK and Cyclins which drive proliferation and the significance to response to CDK4/6 inhibitors. Breast cancer cells harbor heterogeneity in the requirement for a given G1/S regulatory CDK or Cyclin. These dependencies are conditioned by the expression of the respective CDK or Cyclin, as well as other gene expression or genetic features present within the tumor that could represent putative biomarkers. In general, conventional dependency for CDK4 and Cyclin D1 is strongest in HR+/HER2- breast cancer models, whereas TNBC exhibits dependency on a variety of different CDK or Cyclin genes. Resistance to CDK4/6 inhibitors in HR+/HER2- breast cancer models, while occurring through a number of different primary mechanisms, functionally deregulates the phosphorylation of RB. However, genetically enforcing RB activation is sufficient to block proliferation, underscoring the opportunity to ameliorate resistance to CDK inhibitory strategies. CRISPR screens in HR+/HER2- and TNBC models are identifying new mediators of sensitivity and resistance to CDK4/6 inhibitors. Inherently, elevated expression of Cyclin E and p16INK4A are associated with resistance to multiple therapeutic approaches, including CDK4/6 inhibitors, but denote a requirement for CDK2. The cell cycle conditions disparately dependent on CDK4/D1 vs. CDK2/E can be visualized by multispectral imaging and used to direct CDK inhibitor based strategies. CONCLUSIONS: Together these studies illustrate the complex nature of breast cancer cell cycles which can confound therapy. However, understanding of this heterogeneity can create new opportunities for precision approaches targeting CDK/Cyclin-dependence therapeutically. Citation Format: Erik S. Knudsen, Vishnu M. Kumarasamy, Jianxin Wang, Agnieszka Witkiewicz. Deciphering the heterogeneity of cell cycle in breast cancer and relevance to clinical application of CDK inhibitors [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-10-01.