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Elucidating mechanisms of resistance to mutant-selective P13Ka inhibitors

Award Number: R37CA299872
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/04/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2031

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Elucidating mechanisms of resistance to mutant-selective P13Ka inhibitors - PIK3CA mutations are among the most common oncogenic drivers in solid tumors, present in approximately 40% of hormone receptor–positive metastatic breast cancers (HR+ MBC). Orthosteric PI3Kα-selective inhibitors, alpelisib and inavolisib, have received FDA approval for this subset of patients. However, their clinical efficacy is limited by a narrow therapeutic window, driven by on-target toxicities and insulin feedback loop–mediated resistance. Our recent work has demonstrated that reactivation of the PI3K/AKT pathway is a major mechanism of acquired resistance—identified in nearly 50% of patients—primarily through secondary PIK3CA mutations, as well as PTEN loss and activating AKT1 mutations. To address these limitations, novel allosteric, mutant-selective PI3Kα inhibitors have been developed, offering improved target selectivity, reduced toxicity, and a broader therapeutic index. Early-phase clinical trials led by our group have shown encouraging clinical activity and a favorable safety profile relative to orthosteric inhibitors. Nevertheless, resistance to these agents remains inevitable. Our preliminary clinical and preclinical data suggest that acquired resistance to allosteric inhibitors arises through emerging genomic alterations, while de novo resistance is often mediated by baseline co- alterations in the PI3K/PTEN/AKT pathway and adaptive feedback through wild-type PIK3CA signaling or bypass signaling. We hypothesize that rational combination strategies employing horizontal or vertical inhibition of the PI3K pathway can both prevent the emergence of acquired resistance and overcome primary resistance to mutant-selective PI3Kα inhibitors. Our proposed studies aim to: (1) define the genomic landscape of resistance to allosteric PI3Kα inhibitors; (2) functionally characterize resistance mechanisms using in vitro and in vivo models; and (3) develop and test rational combinatorial therapeutic strategies to enhance durability of response. The findings will inform precision patient selection and guide the design of effective combination therapies to maximize clinical benefit from mutant-selective PI3Kα inhibitors in HR+ MBC.


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 = $634,378 )
2026	2026	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Cancer Treatment Research	000	1	9/4/2026	NEW	$634,378
														Subtotal = $634,378

Grand Total All Awards = $634,378

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Elucidating mechanisms of resistance to mutant-selective P13Ka inhibitors

Award Number: R37CA299872

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/04/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2031

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