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

Award Number: R21CA313397
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/04/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2028

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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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $426,828 )
2026	2026	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cancer Treatment Research	000	1	5/5/2026	NEW	$426,828
														Subtotal = $426,828

Grand Total All Awards = $426,828

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

Award Number: R21CA313397

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 05/04/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2028

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