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Targeting molecular mechanisms of the adeno-to-squamous transition in non-small cell lung cancer treatment adaptation

Award Number: R01CA296978
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/16/2025
PERIOD OF PERFORMANCE END DATE: 12/31/2029

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Targeting molecular mechanisms of the adeno-to-squamous transition in non-small cell lung cancer treatment adaptation - SUMMARY Transdifferentiation is a common mode of cellular plasticity in resistance to targeted therapy, and is observed histologically across multiple cancer types, including LUAD-to-small-cell lung cancer, enabling resistance to EGFR inhibitors. There is a growing recognition that the adaptive process taken by cancer to thwart therapy has a non-genetic component, thus requiring the determination of new avenues of therapy. In LUAD, KRAS was long thought to be undruggable, however, two inhibitors received FDA approval three years ago. Though these inhibitors contributed to a response rate of 40% improving clinical outcomes, patients inevitably relapse, with a subset of the tumors adapting to KRAS inhibition by non-genetic mechanisms. In 2020, members of our team discovered that in response to one of the KRAS inhibitors – adagrasib – the tumors of a subset of patients undergo an adeno-to-squamous transition (AST). In this proposal we formulate a comprehensive research program aimed at dismantling AST as an escape route for cancer to adagrasib treatment, by blocking its required chromatin regulators and by decoupling it from the induction of resistance programs. In our preliminary studies, we established mouse and organoid models and found evidence that disruption of specific chromatin regulators either genetically or pharmacologically modulates cellular state along the AST spectrum. This has led us to hypothesize that a screen of chromatin remodelers will reveal AST vulnerabilities. In Aim 1, we carry out a Perturb-Seq screen coupled with a scMultiome approach to identify the specific regulators and then target these with small molecule inhibitors. Finally, we test the translational potential of these inhibitors to block the transition in human patient derived xenografts. A second major finding that we address here is that the squamous histology alone is not sufficient to confer drug resistance to adagrasib, suggesting that additional molecular pathways are required for the adaptive process. This has led us to hypothesize that drug resistance is caused by the sequential induction of first the resistance programs and then a lineage state transition. A prediction of this hypothesis is that distinct lineage states are compatible with unique resistance programs, and thus we seek to systematically decouple this relationship to reveal the specific dependencies of each lineage state. In Aim 2, we leverage a dropout CRISPR-method approach to identify regulators of resistance for both the intermediate and the squamous lineage state along AST, and then we systematically test for the sufficiency and necessity of both the lineage state and resistance programs in modulating the response to KRAS inhibition. We then more broadly test for the expression and clinical relevance of resistance programs in primary human lung adenocarcinoma tumors and how they relate to the host lineage states. Overall the impact of this research is to identify new therapeutic vulnerabilities of lineage states along AST – an important and unaddressed clinical problem – by dissecting the relationship between lineage state and resistance programs.


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 = $703,408 )
2026	2026	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Treatment Research	000	2	12/16/2025	NON-COMPETING CONTINUATION	$633,067
2026	2026	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Treatment Research	001	2	4/16/2026	NON-COMPETING CONTINUATION	$70,341
														Subtotal = $703,408

Issue Date FY: 2025 ( Subtotal = $703,410 )
2025	2025	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Treatment Research	000	1	1/16/2025	NEW	$703,410
														Subtotal = $703,410

Grand Total All Awards = $1,406,818

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Targeting molecular mechanisms of the adeno-to-squamous transition in non-small cell lung cancer treatment adaptation

Award Number: R01CA296978

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/16/2025

PERIOD OF PERFORMANCE END DATE: 12/31/2029

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