Jumonji KDM5 enzymes mediate resistance to CDK4/6 inhibitors in Breast Cancer

Summary We have identified a novel epigenetic susceptibility mediated by Jumonji enzymes that is acquired by ER+ breast cancers as they become resistant to CDK4/6 inhibitors. Preliminary data in multiple models indicates that as breast cancer cells and tumors become progressively more resistant to palbociclib, they become more dependent on enzymes that help them adapt, the targetable Jumonji histone demethylases. Cdk inhibitor- resistant breast cancers, especially those lacking functional pRB, are therefore hypersensitive to inhibitors of Jumonji histone demethylase enzymes. These enzymes are upregulated during the development of drug tolerance and therapeutic resistance and we think they are necessary for the transcriptional adaptability that allows cells to survive therapeutic stress. Resistant cells are exquisitely sensitized to Jumonji enzyme inhibitors in culture while they no longer respond to cdk inhibition. In the present application, our objective is to validate and translate these observations in three important ways: i) by testing the sensitivity of cdk inhibitor resistant cell lines, organoids and patient derived xenografts to our Jumonji inhibitors, ii) by identifying the epigenetic mechanisms underlying this response and iii) by evaluating if Jumonji genetic or pharmacological inhibition can prevent the emergence of drug tolerance and the development of resistance to CDK4/6 inhibitors in ER+ breast cancer. Our efforts can lead to immediate clinical translation since Jumonji inhibitors have just entered clinical trials. Project Number: 1R21CA313397-01 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: ELISABETH MARTINEZ | Institution: UT SOUTHWESTERN MEDICAL CENTER, DALLAS, TX | Award Amount: $426,828 | Activity Code: R21 | Study Section: Special Emphasis Panel[ZRG1 CTH-X (81)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11354606