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Mutation specific pan-KRAS inhibitor signaling responses and anti-tumor effect

Award Number: K22CA292325
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 09/03/2025
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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Mutation specific pan-KRAS inhibitor signaling responses and anti-tumor effect - KRAS is one of the most commonly mutated proteins in cancer and efforts to directly inhibit its function have been ongoing for decades. The most successful of these efforts has been the development of covalent allele specific inhibitors that trap KRAS G12C in its inactive conformation and suppress tumor growth in patients. Whether inactive state selective inhibition can be employed to therapeutically target non-G12C KRAS mutants remains under investigation. We have recently discovered and characterized a non-covalent inhibitor that binds preferentially and with high affinity to the inactive state of KRAS, while sparing NRAS and HRAS. Our study suggests that most KRAS oncoproteins cycle between an active and inactive state in cancer cells and the inhibitor can prevent activation of wild-type and a broad range of KRAS mutants, including G12A/C/D/F/V/S, G13C/D, Q61H, K117N and A146V/T. Based on preliminary results and through comprehensive genetic, biochemical, transcriptomic and proteomic approaches, I will now study the regulation of different KRAS oncoproteins in cancer cells and identify optimal therapeutic applications. In this proposal I will aim to identify mutant specific features (aim 1), regulators (aim 2), and combination therapy (aim 3) throughout KRAS mutant cell lines and mouse models using the pan-KRAS inhibitor (KRASi) described above. The impact of the proposed work here will provide new insight into molecular and biochemical properties of KRAS oncoproteins in cancer. The training component described in the proposed work includes activities to facilitate my transition to an independent principal investigator position. During the K22 phase, I will attend courses, gain hands on experience in order to learn new techniques and attend meetings to expand my network for future collaborations. This award will provide me with the necessary resources and expertise to ensure the successful completion of the training phase of the grant, so that I can transition to a productive career as an independent and well-rounded principal investigator.


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 = $188,351 )
2026	2026	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Research Manpower	000	2	8/11/2026	NON-COMPETING CONTINUATION	$188,351
														Subtotal = $188,351

Issue Date FY: 2025 ( Subtotal = $188,351 )
2025	2025	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Research Manpower	000	1	9/2/2025	NEW	$188,351
														Subtotal = $188,351

Grand Total All Awards = $376,702

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Mutation specific pan-KRAS inhibitor signaling responses and anti-tumor effect

Award Number: K22CA292325

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 09/03/2025

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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