Abstract 5975: Discovery of mechanisms that modulate the hippo pathway and CDK6 expression in CDK4/6 inhibitor resistant breast cancer cells

Abstract

Abstract Hormone positive (HR+) breast cancer is the most common subtype in this population. The current standard of care in advanced HR+ breast cancer includes endocrine therapy (tamoxifen, aromatase inhibitors, etc) and CDK4/6 inhibitors. CDK4/6 inhibitors significantly prolong survival and is now the general accepted choice of drug in first line. Despite the enormous clinical benefit, there remains a substantial portion of patients who ultimately develop resistance against CDK4/6 inhibitors. Many mechanisms have been proposed for CDK4/6 inhibitor resistant, including upregulation of CDK4, CDK6, Cyclin E, and others. Recently studies have linked the hippo pathway to CDK6 upregulation and resulting in CDK4/6 inhibitor resistance. We have set up a kinase library screen for kinase inhibitors that downregulate CDK6 amplification and further assess for reversal of resistance. We discovered staurosporine and the PI3K inhibitor PIK-75 as small molecules that potently downregulate CDK6 expression in breast cancer cells. We further confirmed that these compounds reverse the resistance towards CDK4/6 inhibitors in CDK6 amplification cells. By kinase profiling combined with a small hairpin RNA (shRNA) screen, we discovered the mechanisms that resulted in CDK6 downregulation and modulation of the hippo pathway to reverse the CDK4/6 inhibitor resistance. Our discovery has implications for therapeutic development in this group of patients posing a huge unmet need. Citation Format: Chung-Jen Yu, Yong-Ji Zhuang, Ting-Yi Lin, Ta-Chung Chao, Chun-Yu Liu, Ling-Ming Tseng, Jiun-I Lai. Discovery of mechanisms that modulate the hippo pathway and CDK6 expression in CDK4/6 inhibitor resistant breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5975.