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Exploring ATR as a Novel Vulnerability of Osimertinib-Resistant EGFR-Driven Lung Adenocarcinomas

Award Number: F31CA301804
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 04/07/2026
PERIOD OF PERFORMANCE END DATE: 04/06/2028

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Exploring ATR as a Novel Vulnerability of Osimertinib-Resistant EGFR-Driven Lung Adenocarcinomas - PROJECT SUMMARY Osimertinib (osi), a third-generation EGFR tyrosine kinase inhibitor (TKI), has significantly improved outcomes for patients with EGFR-mutant lung cancer, but resistance is inevitable, and it is not curative. Understanding the mechanisms driving resistance is critical to developing more effective treatments. Emerging evidence suggests that osi induces replication stress. I am investigating ATR, a kinase activated by replication stress, for its role in promoting cell cycle progression after osi treatment. Additionally, osi-induced replication stress may sensitize tumors to DNA-damaging chemotherapy by overwhelming DNA repair machinery. Consistently, recent clinical trials have shown that combining osi with chemotherapy improves progression-free survival, and trastuzumab deruxtecan (TDXd), the only antibody-drug conjugate approved in lung cancer, is effective against EGFR-TKI- resistant tumors. The central hypothesis of this study is that osi-induced replication stress activates ATR to attenuate this stress and promote cell cycle progression, leading to resistance. Furthermore, ATR inhibition and TDXd is expected to delay tumor relapse following osi treatment. Using patient-derived models, this project will: Aim 1) determine if ATR is necessary to promote cell cycle progression during the acquisition of osi resistance and identify ATR-dependent pathways mediating this process. Aim 2) will evaluate if residual tumors persisting after osi treatment exhibit elevated replication stress and ATR activity, and whether ATR inhibition and TDXd can delay relapse. Human tumors treated with EGFR-TKIs, +/- chemotherapy, will also be profiled using imaging mass spectrometry (IMC) to detect if DNA damage repair (DDR) activity correlates with treatment response and predict sensitivity to ATR inhibition and TDXd. This research will address the critical need to understand the role of ATR activity in osi resistance and provide novel insights into the presence of DDR in human tumors. Together these insights will explore the clinical potential of ATR inhibitors and TDXd for treating EGFR-mutant tumors. The project will utilize Yale School of Medicine’s (YSM) state-of-the-art facilities, confocal microscopes from the Yale Center for Cellular and Molecular Imaging (CCMI) and a Cytometry Time-Of-Flight (CyTOF) Helios Imaging Mass Cytometer for the IMC study. Access to patient-derived cell lines (PDCs) and xenograft tissues (PDXs) from the Yale Advanced-Stage Lung Cancer Tissue Collection Study, managed by the Sponsor, will further facilitate this research. This F31 Fellowship will provide the Principal Investigator (PI) with essential training in advanced techniques such as mass spectrometry and IMC while supporting the PI's development in translational research skills and scientific communication. Additionally, acquiring this training is crucial for the PI who intends to pursue a future career studying therapeutic biomarkers, that target synthetic lethal interactions, to bridge gaps in cancer patient care with translational research. Leveraging the F31 Fellowship to maximize resources and training will ensure the project's success and support the PI’s growth into an independent researcher.


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 = $35,134 )
2026	2026	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Research Manpower	001	1	4/7/2026	NEW	$0
2026	2026	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Research Manpower	000	1	4/7/2026	NEW	$35,134
														Subtotal = $35,134

Grand Total All Awards = $35,134

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Exploring ATR as a Novel Vulnerability of Osimertinib-Resistant EGFR-Driven Lung Adenocarcinomas

Award Number: F31CA301804

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 04/07/2026

PERIOD OF PERFORMANCE END DATE: 04/06/2028

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