Thursday, January 29, 2026 1/29/2026

Preventing adaptive drug resistance through Mediator kinase inhibition

Award Number: R01CA266027
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2022
PERIOD OF PERFORMANCE END DATE: 07/31/2027

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Preventing adaptive drug resistance through Mediator kinase inhibition - Cancer drug resistance is driven in part by the plasticity of tumor cells that allows for therapy-induced adaptation of their transcriptional program. This adaptive drug resistance is associated with the acquisition of various phenotypic changes that promote tumor growth, metastasis and resistance to other therapies. Experimental drugs targeting CDK8/19 Mediator kinase that regulates transcriptional reprogramming were found to suppress the development of resistance to different classes of targeted and conventional anticancer agents. We hypothesize that the emergence of adaptive drug resistance in vitro and in vivo, with concurrent acquisition of tumor-promoting phenotypes, can be prevented by inhibiting Mediator kinase. We will test this hypothesis in HER2-positive breast cancers by analyzing the effects of Mediator kinase inhibition on the emergence of resistance to a HER2-targeting drug (lapatinib) and a conventional drug (paclitaxel). We will pursue the following Specific Aims. (1) The effect of Mediator kinase deficiency on the development of adaptive drug resistance in vitro will be analyzed by generating derivatives of HER2-positive human breast cancer cell lines that will express wild-type or kinase-dead Mediator kinase and by analyzing the effects of Mediator kinase mutagenesis or treatment with selective CDK8/19 inhibitors on the emergence of adaptive resistance to lapatinib or paclitaxel. Comprehensive phenotypic, genomic and transcriptomic analyses will be used to evaluate the effect of drug adaptation and Mediator kinase inhibition on the acquisition of tumor-promoting phenotypes and to identify signal transduction pathways, inhibitors of which could be combined with CDK8/19 inhibitors to enhance the prevention of resistance. (2) HER2-positive human cell lines with different Mediator kinase status and a panel of HER2- positive breast cancer patient-derived xenografts (PDX) will be selected for lapatinib and paclitaxel resistance in vivo, to compare the resistance-preventing effects of Mediator kinase deficiency in tumor cells alone and with the effects of its pharmacological inhibition in both tumor and stromal cells. Transcriptomic and phenotypic analysis will be used to delineate the effects of drug selection and Mediator kinase inhibition on gene expression in tumor and stromal cells. Whole exome sequencing of PDX tumors will reveal if Mediator kinase inhibition prevents the emergence of new drug-resistant tumor lineages or suppresses the growth of drug-resistant cells that may pre-exist in heterogeneous PDXs. (3) The effects of Mediator kinase on the emergence of drug resistance will also be investigated in a murine Her2/Neu-driven mouse mammary carcinoma cells adapted for syngeneic growth, both in vitro (as in Aim 1) and in vivo using both immunocompetent and immunodeficient hosts. This analysis will elucidate the effect of the host immune system on drug adaptation and the role of Mediator kinase in this effect. The proposed program will delineate the roles of Mediator kinase in tumor adaptation to treatment, in vitro and in vivo, and will indicate whether Mediator kinase-inhibiting drugs may be able to extend the duration of remission induced by cancer therapy.


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 = $0 )
2026	2025	UNIVERSITY OF SOUTH CAROLINA	1600 HAMPTON ST	COLUMBIA	SC	29208	RICHLAND	USA	Cancer Treatment Research	000	4	12/24/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $609,336 )
2025	2025	UNIVERSITY OF SOUTH CAROLINA	1600 HAMPTON ST	COLUMBIA	SC	29208	RICHLAND	USA	Cancer Treatment Research	000	4	7/8/2025	NON-COMPETING CONTINUATION	$609,336
														Subtotal = $609,336

Issue Date FY: 2024 ( Subtotal = $582,679 )
2024	2024	UNIVERSITY OF SOUTH CAROLINA	1600 HAMPTON ST	COLUMBIA	SC	29208	RICHLAND	USA	Cancer Treatment Research	000	3	7/2/2024	NON-COMPETING CONTINUATION	$582,679
														Subtotal = $582,679

Issue Date FY: 2023 ( Subtotal = $596,858 )
2023	2023	UNIVERSITY OF SOUTH CAROLINA	1600 HAMPTON ST # 414	COLUMBIA	SC	29208	RICHLAND	USA	Cancer Treatment Research	000	2	7/10/2023	NON-COMPETING CONTINUATION	$596,858
														Subtotal = $596,858

Issue Date FY: 2022 ( Subtotal = $607,349 )
2022	2022	UNIVERSITY OF SOUTH CAROLINA	1600 HAMPTON ST # 414	COLUMBIA	SC	29208	RICHLAND	USA	Cancer Treatment Research	000	1	7/19/2022	NEW	$607,349
														Subtotal = $607,349

Grand Total All Awards = $2,396,222

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Preventing adaptive drug resistance through Mediator kinase inhibition

Award Number: R01CA266027

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2022

PERIOD OF PERFORMANCE END DATE: 07/31/2027

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