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Targeting S6K2 to Overcome Drug Resistance in NRAS-mutant Melanoma

Award Number: R01CA268510
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2022
PERIOD OF PERFORMANCE END DATE: 08/31/2027

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Targeting S6K2 to Overcome Drug Resistance in NRAS-mutant Melanoma - PROJECT SUMMARY While several therapies have been approved for melanoma, there are limited treatment options for NRAS mutant (NRASmut) tumors, which account for ~30% of all melanomas. NRASmut tumors are extremely aggressive and are associated with poor patient survival. These types of tumors are highly resistant to available targeted therapies and are poorly responsive to immunotherapies. Therefore, there is an urgent unmet need to identify novel targets and effective therapies to help this large population of melanoma patients who do not respond to currently available treatments. Our goal is to identify critical vulnerabilities that can be targeted to offset drug resistance in NRAS mutant melanoma. Oncogenic NRAS activates both the MAPK and PI3K pathways. However, inhibiting either pathway alone is barely effective in patients and co-targeting both pathways leads to unacceptable toxicities in patients. We previously reported that BRAF-mutant melanomas resistant to BRAF and MEK inhibitors (MAPKi-R) have sustained activation of the ribosomal protein S6 kinase. We have now discovered that MAPKi-R NRASmut melanomas rely on the S6K2 isoform for survival. Selective S6K2 blockade, in the context of active S6K1, perturbs redox and lipid metabolism, triggering lethal lipid peroxidation in NRASmut melanoma cells that are resistant to MAPK inhibition. Based on our preliminary findings, we postulate that S6K2 controls metabolic and redox homeostasis, and melanoma cell survival, thereby constituting a novel and promising therapeutic target. As S6K is a node of convergence of the MAPK and PI3K/mTOR pathways, we further posit that selectively blocking S6K2 can overcome resistance to MAPKi mediated by broad molecular mechanisms that rely on these pathways. In this project we will define the mechanism whereby S6K2-dependent lipid and redox homeostasis contributes to drug resistance and promotes survival of MAPKi-R melanoma. Furthermore, we will exploit the dependency of melanoma on S6K2 to offset MAPKi resistance. Our proposed strategy, which is significantly different from MAPK/PI3K inhibition, will enable functional precision by targeting a convergent subnetwork representing a vulnerability selectively in tumor cells. We anticipate that our studies will provide a mechanistic framework to inform the design of therapeutic strategies targeting S6K2 directly, or alternatively, S6K2 specific effector pathways and improve the outcomes of NRASmut melanoma patients and possible other types of RAS-mutant tumors.


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 = $977,758 )
2025	2025	THE WISTAR INSTITUTE OF ANATOMY AND BIOLOGY	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Treatment Research	001	4	9/1/2025	EXTENSION WITH OR WITHOUT FUNDS	$977,758
2025	2024	THE WISTAR INSTITUTE OF ANATOMY AND BIOLOGY	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Treatment Research	000	3	9/1/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $977,758

Issue Date FY: 2024 ( Subtotal = $464,112 )
2024	2024	THE WISTAR INSTITUTE OF ANATOMY AND BIOLOGY	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Treatment Research	000	3	7/31/2024	NON-COMPETING CONTINUATION	$464,112
														Subtotal = $464,112

Issue Date FY: 2023 ( Subtotal = $475,922 )
2023	2023	THE WISTAR INSTITUTE OF ANATOMY AND BIOLOGY	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Treatment Research	000	2	8/29/2023	NON-COMPETING CONTINUATION	$475,922
														Subtotal = $475,922

Issue Date FY: 2022 ( Subtotal = $522,753 )
2022	2022	WISTAR INSTITUTE OF ANATOMY AND BIOLOGY, THE	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Treatment Research	000	1	8/31/2022	NEW	$522,753
														Subtotal = $522,753

Grand Total All Awards = $2,440,545

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Targeting S6K2 to Overcome Drug Resistance in NRAS-mutant Melanoma

Award Number: R01CA268510

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2022

PERIOD OF PERFORMANCE END DATE: 08/31/2027

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