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Elucidating mechanisms underlying lung cancer lineage plasticity thatfacilitate adaptation and resistance to targeted therapy

Award Number: R01CA305978
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/02/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2031

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Elucidating mechanisms underlying lung cancer lineage plasticity thatfacilitate adaptation and resistance to targeted therapy - Project Summary Advanced EGFR mutant lung adenocarcinoma (LUAD) is treated with EGFR tyrosine kinase inhibitors (TKIs). While effective, virtually all patients progress on therapy. Mechanisms known to cause acquired EGFR TKI resistance include secondary EGFR mutations, activation of bypass signaling pathways, or histological transformation to lineage variants no longer dependent on EGFR signaling. Mechanisms of acquired EGFR TKI resistance have been identified in only about half of the cases examined, however, despite extensive DNA sequencing efforts. Transcriptional adaptations enabling LUAD cells to survive and proliferate during therapy are emerging as a prerequisite for many forms of acquired EGFR TKI resistance. The overarching hypothesis addressed in this grant proposal is that reversible and dynamic transcriptional adaptations accelerate acquired EGFR TKI resistance in LUAD, and blocking this transcriptional plasticity will improve EGFR TKI treatment outcomes. While transcriptional adaptations have been defined in experimental models and clinical samples, the pathways and mechanisms regulating transcriptional plasticity itself remain largely unknown. This is a significant gap because transcriptional plasticity controls how fast and how well LUAD cells adapt to EGFR TKI treatment. The primary goal of this application is to fill this gap. Aim 1 tests the novel concept that loss of the RB1 tumor suppressor gene (Rb) accelerates acquired EGFR TKI resistance by driving transcriptional plasticity. Rb loss is suggested to de-repress retroelements inducing chronic, cancer cell intrinsic inflammatory signaling. Inflammatory signaling then drives plasticity and EGFR TKI resistance. Aim 2 tests the innovative idea that initial adaptation to EGFR TKI is driven by YAP/TEAD/β-catenin mediated reprogramming of LUAD cells to a quiescent, alveolar transcriptional state. This alveolar state is extinguished in favor of other transcriptional adaptations as cells progress through therapy. While parallel and distinct, the aims are complementary and interconnected. Both aims address the role of Rb in altering the trajectory of LUAD transcriptional adaptations during EGFR TKI therapy. Both aims interrogate the impact of specific signaling pathways on transcriptional plasticity and EGFR TKI responses. Each aim employs cutting edge experimental models unique to this research team, including genetically engineered mouse models. Use of these animal models is required to experimentally assess the complex interactions between cancer cells and normal cells within a physiological tumor growth environment that can impact acquired therapeutic resistance and cancer progression. Each aim is led by a different MPI with complementary expertise. Collaboration between aims creates synergies by sharing experimental models, technical expertise, data, and patient specimens. Successful completion of the work will advance fundamental understanding of LUAD phenotypic plasticity and acquired EGFR TKI resistance while identifying targets for future therapeutic intervention.


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 = $719,951 )
2026	2026	HEALTH RESEARCH, INC.	665 ELM ST	BUFFALO	NY	14203	ERIE	USA	Cancer Biology Research	000	1	6/5/2026	NEW	$719,951
														Subtotal = $719,951

Grand Total All Awards = $719,951

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Elucidating mechanisms underlying lung cancer lineage plasticity thatfacilitate adaptation and resistance to targeted therapy

Award Number: R01CA305978

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/02/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2031

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