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Synthetic lethal targeting of KRAS/KEAP1 co-mutant non-small cell lung cancer

Award Number: R01CA285743
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/03/2024
PERIOD OF PERFORMANCE END DATE: 06/30/2029

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Synthetic lethal targeting of KRAS/KEAP1 co-mutant non-small cell lung cancer - Abstract Activating KRAS mutations occur in 20-40% of non-small cell lung cancers (NSCLCs). About 20% of the KRAS mutation tumors have co-occurring mutations of KEAP1 that are resistant to most therapies and difficult to treat. Therefore new treatments are needed. Currently, we found these co-mutant tumors express high levels of the histone deacetylase protein HDAC4 important for their survival. KRAS/KEAP1 co-mutant NSCLC cells are sensitive to a HDAC4/5 inhibitor called LMK235 while single mutant cells are not. Knockdown of HDAC4/5 or treatment with TSA (inhibits Class I/II HDACs including HDACs 4 and 5) has similar effect. Thus, high HDAC expression represents an Achilles heel that renders co-mutant cells sensitive to LMK235 and HDAC4/5 inhibition. Mechanistically, we found LMK235 induces toxicity by activating a tumor suppressor protein called RB and by activating a protein called BIM that triggers cell death. Lastly, we found LMK235 causes striking synergistic toxicity when combined with the drug AMG510 (sotorasib) in KRASG12C/KEAP1 co-mutant NSCLCs. AMG510 specifically inhibits the KRAS G12C mutant and is FDA approved. In clinical studies, KRAS G12C/KEAP1 mutant NSCLC tumors responded less well to AMG510 than KRAS G12C tumors with wild-type KEAP1. This highlights a need to improve treatments in these tumors. The finding that LMK235 causes synergistic toxicity with AMG510 suggests this drug combination could improve responses in these patients. In Aim 1 we will establish that LMK235 and TSA specifically target KRAS/KEAP1 co-mutant and not single mutant NSCLC cells. We will determine how RB is activated by LMK235 and confirm its role. The role of BIM and BIM acetylation will also be determined by creating mutants of BIM that either block or inhibit acetylation and testing their effect in cell responses to LMK235. In Aim 2 we will examine the combined effects of AMG510 and LMK235. First, we will establish that the combination of AMG510+LMK235 specifically targets KRASG12C/KEAP1 co- mutant cells. This will be done by comparing sensitivity in a panel of NSCLC cell lines that vary in KRASG12C and KEAP1 status, and by generating cell lines where KRASG12C and/or KEAP1 are mutated. Lastly we will test the response of KRASG12C/KEAP1 double or single mutant tumors to AMG510+LMK235 in mice. The impact and significance of the proposed studies is high. KRAS/KEAP1 co-mutant NSCLCs are difficult to treat. The current grant identifies HDAC4/5 as a targetable vulnerability in these cancers. LMK235 induces toxicity uniquely in KRAS/KEAP1 co-mutant NSCLCs but not single muant NSCLCs, and therefore could be a way to target these double mutant cancers. The grant is also clinically relevant, as KRASG12C/KEAP1 mutant NSCLCs responded less well to the G12C inhibitor AMG510 in clinical studies than KRASG12C tumors with wild-type KEAP1. The grant shows LMK235 in combination with AMG510 causes striking synergistic killing specifically in KRAS/KEAP1 co-mutant NSCLC. Thus, combination of AMG510 with LMK235 (or compounds like it) could be used to improve responses in these patients.


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: 2025 ( Subtotal = $340,215 )
2025	2025	RUSH UNIVERSITY MEDICAL CENTER	1653 W CONGRESS PKWY	CHICAGO	IL	60612	COOK	USA	Cancer Treatment Research	000	2	5/27/2025	NON-COMPETING CONTINUATION	$340,215
														Subtotal = $340,215

Issue Date FY: 2024 ( Subtotal = $340,215 )
2024	2024	RUSH UNIVERSITY MEDICAL CENTER	1653 W CONGRESS PKWY	CHICAGO	IL	60612	COOK	USA	Cancer Treatment Research	000	1	7/3/2024	NEW	$340,215
														Subtotal = $340,215

Grand Total All Awards = $680,430

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Synthetic lethal targeting of KRAS/KEAP1 co-mutant non-small cell lung cancer

Award Number: R01CA285743

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/03/2024

PERIOD OF PERFORMANCE END DATE: 06/30/2029

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