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Role of ABL kinases in regulating DNA damage repair and transcription-replication conflicts in SCLC tumors

Award Number: F31CA318166
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2029

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Role of ABL kinases in regulating DNA damage repair and transcription-replication conflicts in SCLC tumors - ABSTRACT. Small cell lung cancer (SCLC) is a highly aggressive lung cancer that is often metastatic when diagnosed. Few therapies have yielded lasting effects, as SCLC patients experience recurrence with low survival. Identifying novel molecular targets of SCLC is necessary for therapeutic development. Recent data from our laboratory has shown that treating SCLC tumors in mouse models with FDA-approved ABL kinase inhibitors led to a decrease in metastatic disease and promoted animal survival. Further, treating SCLC cells with ABL allosteric inhibitors dysregulated proteins in the transcription-coupled homologous recombination (TC-HR) pathway, a process that repairs DNA double-stranded breaks (DSBs). SCLC cells exhibit high levels of genomic instability and often have upregulated expression of TC-HR proteins, suggesting dependence on TC-HR for survival. TC-HR is promoted by transiently expressed R-loops, which are DNA-RNA hybrids that can contribute to genomic instability. In cells with defective TC-HR, R-loop accumulation can induce transcription-replication conflicts (TRCs) and enhance DNA damage, thereby revealing a potential vulnerability of SCLC cells to drugs targeting the replication stress response. We showed that SCLC cells undergo DNA damage upon treatment with ABL kinase inhibitors or degraders. Notably, I found that ABL inhibition induces TRCs in cells with active transcription. ABL interactome datasets revealed that DDX5, an RNA helicase that promotes R-loop resolution, is a predicted substrate of ABL kinases. DDX5 gene expression is upregulated in SCLC compared to other cancer types. I found that ABL inhibition led to decreased DDX5 protein levels. The role for ABL kinase activity in regulating the RNA helicase activity of DDX5 in SCLC cells has not yet been explored. This proposal will evaluate the hypothesis that SCLC tumors are dependent on ABL kinases to induce DNA damage-repair, and that ABL inhibition promotes increased DNA damage through defective DNA repair and accumulation of TRCs mediated in part by DDX5. Thus, I propose to (1) define the mechanisms of ABL kinase-inhibition mediated DNA damage in SCLC, and (2) assess ABL-mediated DDX5 activity in response to DNA damage in SCLC using in vitro cell culture and in vivo mouse models. These studies will uncover the mechanisms by which ABL inhibition regulates TRCs and DNA damage-repair pathways in SCLC cells and identify molecular targets to treat SCLC tumors with novel combination therapies to enhance therapeutic efficacy for patients with metastatic SCLC. Training plan: I will receive training and support in R-loop profiling and in vivo mouse work. Further, I will build my computational skill set through coursework offered at Duke University, gain professional experience at a biomedical or pharmaceutical research company through the Department of Pharmacology and Cancer Biology internship program, and broaden my network and refine my communication skills through presentations at conferences. This research and training environment at Duke will facilitate the successful completion of the proposed project and my development in pursuing a research career in industry.


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 = $43,742 )
2026	2026	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Cancer Research Manpower	000	1	8/11/2026	NEW	$43,742
2026	2026	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Cancer Research Manpower	001	1	8/11/2026	NEW	$0
														Subtotal = $43,742

Grand Total All Awards = $43,742

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Role of ABL kinases in regulating DNA damage repair and transcription-replication conflicts in SCLC tumors

Award Number: F31CA318166

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2029

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