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Targeting a novel covalent RAS dimer in RASQ61 mutants-driven cancers

Award Number: K01CA313805
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 05/07/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2029

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Targeting a novel covalent RAS dimer in RASQ61 mutants-driven cancers - PROJECT SUMMARY (30 line limit) RAS mutations drive a substantial proportion (20~30%) of deadly tumors. Two KRASG12C inhibitors, sotorasib and adagrasib, are now approved, justifying the feasibility of direct targeting RAS. Despite this achievement, approved KRASG12C inhibitors do not address other oncogenic RAS alleles, such as the hotspot Q61 mutations (e.g. Q61H, Q61K, Q61L, and Q61R). Thus, a deeper understanding of fundamental RAS mechanisms and functions is essential for effectively tackling RAS-driven diseases. RAS transmits signals through protein-protein interactions controlled by nucleotide binding state. These interactions are thought to occur within multi- component signalosomes that form when RAS is bound to the cell membrane and various RAS effector proteins. We have published two structural models (Cell and Nat Struct Mol Biol) for membrane-bound KRAS protein complexes, validated in biological systems, while other models have been proposed without biological validation yet. The transient nature of these “complexes,” makes them difficult to isolate and study. This proposal aims to characterize the novel, covalent RAS dimer we have observed at the hotspot Q61, and to develop new therapeutic strategies specifically targeting RASQ61 mutants commonly found in human cancers, such as melanoma, leukemia, thyroid cancer, and lung cancer. Based on our preliminary data, we hypothesize that RASQ61 mutants form covalent dimer at differential propensity and are particularly responsive to specific classes of RAF and MEK inhibitors. Therefore, the specific aims of the current proposal are to 1) Determine the prevalence and determinants of the covalent dimer of RASQ61 mutants; 2) Evaluate the impact of RAFi’s and MEKi’s on covalent RAS dimer formation and signaling of RASQ61 mutants; 3) Elucidate the mechanism for RAFi’s and MEKi’s sensitivity in the context of RASQ61 mutants. The overarching goal of this proposal is to develop new therapeutic concepts specifically tailored to RASQ61 mutants (Q61H, Q61K, Q61L, and Q61R) found in cancer patients. Successful completion of this study will characterize Cys118-meidated covalent RAS dimer of Q61 mutants and pinpoint the best RAFi’s and MEKi’s for RASQ61 mutants-driven cancers. This research will set the stage for clinical development of the first RAS biomarker-driven, molecularly targeted RAFi and MEKi therapies, representing a significant and innovative advancement in clinical oncology given the current lack of targeted therapies for RASQ61 mutants-driven cancers. More broadly, this work will expand our fundamental knowledge of how RAS proteins function within larger signaling complexes at the cell membrane.


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 = $131,727 )
2026	2026	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cancer Research Manpower	000	1	5/11/2026	NEW	$131,727
														Subtotal = $131,727

Grand Total All Awards = $131,727

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Targeting a novel covalent RAS dimer in RASQ61 mutants-driven cancers

Award Number: K01CA313805

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 05/07/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2029

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