CCSG Pilot: Targeting Epigenetic Regulation to Overcome CDK4/6i Resistance in Breast Cancer

Abstract CDK4 and CDK6 are crucial drivers of the cell cycle, presenting a significant therapeutic target in various cancers. The FDA has granted ''Breakthrough Therapy'' designation to CDK4/6 inhibitors, which are approved for treating estrogen receptor-positive (ER+) breast cancers. When combined with endocrine therapy, these inhibitors have become the standard first-line treatment for advanced ER+/HER2- breast cancer (BC). Despite these advancements, the efficacy of CDK4/6 inhibitors is limited by both intrinsic and acquired resistance. Therefore, a deeper mechanistic understanding is urgently needed to fully harness their clinical potential. Our preliminary findings reveal a novel mechanism involving epigenome remodeling within CDK4/6 inhibitor-treated breast cancer cells. Specifically, LSD1 transcriptionally increased CDK6 transcription, leading to CDK4/6 inhibitor resistance. Inhibiting LSD1 significantly enhances CDK4/6 inhibitor sensitivity and reverses CDK4/6 inhibitor resistance in vitro. Additionally, LSD1 is highly expressed in CDK4/6i resistant cells. Based on these preliminary insights, we hypothesize that LSD1 promotes CDK4/6 inhibitor resistance. To test this hypothesis, we will not only identify the potential molecular mechanism of LSD1-induced CDK6 expression but also determine whether therapeutic inhibition of LSD1 overcomes CDK4/6 resistance. Our proposal will integrate comprehensive bioinformatics, human samples and xenografts with pharmacological approaches. Translational and clinical relevance: Our proposed study will investigate the mechanism of acquired resistance to CDK4/6i driven by LSD1-induced CDK6 accumulation in BC. We will also examine how LSD1 promotes extensive chromatin accessibility changes in CDK4/6i-resistant cells. Additionally, we will explore whether the co-expression of LSD1 and CDK6 can serve as a biomarker for CDK4/6i resistance. Finally, we will provide evidence supporting a combination therapy strategy that leverages LSD1 inhibitors to enhance the effectiveness of CDK4/6i. Given that LSD1 inhibitors are currently in clinical trials, this research could pave the way for their evaluation as a next-line treatment for CDK4/6i-resistant patients. Our research team will include PI (who is an expert at breast cancer progression, MCO program), breast cancer oncologist Dr. Jones, Veronica M. (who will help to collect breast cancer patient’s samples, TO program) and Dr. Jinpeng Liu (an expert at biostatistics and bioinformatics, MCO program). To perform experiments, we will need to use Biospecimen and Tissue Procurement Shared Resource Facility (BPTP) and Biostatistics and Bioinformatics Shared Resource Facility (BB).