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Repurposing HSP90 inhibitors as a new RTK condensate-directed therapy in cancer

Award Number: R01CA312279
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2031

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Repurposing HSP90 inhibitors as a new RTK condensate-directed therapy in cancer - Gene fusions involving receptor tyrosine kinases (RTKs) such as ALK or RET represent a prominent class of oncogenic driver alterations in lung cancer (~225,000 new patients/year worldwide) and across all cancer subtypes (3-5% of all diagnoses). Despite the success of tyrosine kinase inhibitor (TKI) therapy in prolonging survival, most patients will develop TKI resistance and ultimately die of their disease. We recently discovered a membraneless subcellular structure that functions as an oncogenic signaling hub in cancers driven by major RTK fusion proteins including EML4-ALK and CCDC6-RET. These micron-scale, protein-based structures, which we termed RTK protein granules, locally enrich the upstream RAS GTPase activating complex (GRB2/SOS1/SHP2) and are necessary and sufficient for coordinating downstream oncogenic RAS/MAP Kinase (MAPK) signaling and in vivo tumor growth. These data establish RTK protein granules as a new pathogenic biomolecular condensate in cancer. Here we focused on EML4-ALK and conducted an imaging-based, high-throughput screen of >11,500 compounds to identify EML4-ALK condensate disruptors. Remarkably, 16 of the 20 top hits were distinct inhibitors of the heat shock protein 90 (HSP90i) family, revealing a dramatic class effect. HSP90s are an integral part of the protein chaperone network; canonically, HSP90i reduce the total level of many oncogenic client proteins and have broad anti-tumor activity in cell line and xenograft models, but clinical testing has been disappointing due to the absence of prognostic biomarkers, “on-target” toxicity, and lack of sustained efficacy. This goal of this proposal is to repurpose newer generation HSP90i (PU-H71, TAS-116) as a condensatedirected therapeutic, establishing a new mechanism of action (MOA) for HSP90i with a significantly greater therapeutic window. In Aim 1, we will define the mechanism by which HSP90 inhibition leads to loss of EML4-ALK condensates, addressing a fundamental knowledge gap as to how the protein chaperone networks regulate condensates. In Aim 2, we will test HSP90 inhibition in combination with standard of care ALK TKI as an RTK condensate-directed therapeutic strategy in cancer. The use of vertebrate animals (mouse xenografts) is a prerequisite to launch human clinical trials. Specifically, in vitro cell culture experiments can only provide preliminary indications regarding the success of therapeutic agents and in vivo testing is critical to assess the pharmacokinetic/pharmacodynamic effects of these agents (e.g., granule disruption) and the in vivo therapeutic index. Successful completion of this project will address an important unmet medical need and establish a new conceptual paradigm for how protein chaperone network inhibitors can be repurposed to target the many aberrant biomolecular condensates beyond RTK fusions that regulate the initiation and maintenance of cancer.


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 = $577,331 )
2026	2026	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Treatment Research	000	1	7/27/2026	NEW	$577,331
														Subtotal = $577,331

Grand Total All Awards = $577,331

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Repurposing HSP90 inhibitors as a new RTK condensate-directed therapy in cancer

Award Number: R01CA312279

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2031

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