ABL kinase inactivation induces transcription-replication conflicts and impairs replication fork progression in metastatic small cell lung cancer.
Date
2026-07-15
Journal Title
Journal ISSN
Volume Title
Repository Usage Stats
views
downloads
Citation Stats
Attention Stats
Abstract
Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine cancer that is typically metastatic upon diagnosis and has poor overall survival. Here we report that the inactivation of ABL tyrosine kinases impairs the outgrowth of metastatic SCLC tumors, resulting in prolonged animal survival. ABL inactivation increases the accumulation of transcription-replication conflicts (TRCs), compromises replication fork progression, and impairs the function of proteins implicated in transcription-coupled homologous recombination, including RAD51 and RAD52. Mechanistically, ABL-mediated tyrosine phosphorylation of RAD52 and RAD51 prevents the accumulation of TRCs and promotes replication fork progression, respectively. Because ABL inactivation increased DNA damage, we evaluated whether blocking the activity of DNA damage-repair pathways in the presence of ABL inhibitors might synergize to promote SCLC cell death. Concurrent inactivation of ABL and ATR, the primary responder to replication stress, synergistically inhibits SCLC cell growth in vitro and impairs metastatic outgrowth over single-agent-treated mice. Thus, co-inactivation of ABL and DNA damage-repair pathways might be exploited to inhibit outgrowth of SCLC metastases.
Type
Department
Description
Provenance
Subjects
Citation
Permalink
Published Version (Please cite this version)
Publication Info
Gu, Jing Jin, Kevin M Scott, Arijit Ghosh, Roberto H Barbier, Douglas C Rouse, Jacob P Hoj, Michael W Caminear, Fengqi Zhang, et al. (2026). ABL kinase inactivation induces transcription-replication conflicts and impairs replication fork progression in metastatic small cell lung cancer. Cell Rep, 45(7). p. 117699. 10.1016/j.celrep.2026.117699 Retrieved from https://hdl.handle.net/10161/35399.
This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.
Collections
Scholars@Duke
Michael Caminear
Li Lan
The Lan Lab is dedicated to researching how cancer cells respond to DNA damage through DNA repair mechanisms and developing innovative strategies to target these pathways in cancer therapy. Our significant contributions include uncovering the critical role of PARP in DNA repair, leading to successful applications of PARP inhibitors in the treatment of breast, ovarian, and other types of cancer. We study how DNA responds to oxidative damage at specific chromosomal locations, significantly advancing our understanding of DNA damage response in different chromosomal environments. Furthermore, our recent investigations have revealed a novel mRNA and R-loop-dependent DNA repair pathway that acts as a protective mechanism for the transcribed regions of the genome, introducing a new paradigm in the field of DNA repair research.
Some of the research interests of the Lan Lab:
- Unraveling the underlying mechanisms of mRNA and R-loop-dependent DNA repair (RDDR) in cancer and developing targeted therapies. We actively investigate the molecular mechanisms of the RDDR pathway, including its regulators. We study how the pathway is processed coupling with DNA replication and chromatin remodeling. We employ screening platforms to monitor the RDDR pathway and the function of RDDR proteins, with the goal of developing inhibitors that disrupt RDDR in cancer cells. We try to identify RDDR biomarkers for patient stratification and predict the response to RDDR-targeted therapy. Additionally, we explore its potential applications in gene editing. Our research spans from basic science to translation, with a focus on the potential of mRNA-modifying enzymes as therapeutic targets for treating cancers exhibiting increased genome instability.
- Investigating the response of telomeres to oxidative damage in cancer and exploiting vulnerabilities in cancer cells. By comprehending how cancer cells respond to oxidative damage at telomeres through mechanisms such as telomerase, alternative lengthening of telomeres, and mRNA and R-loop-mediated repair pathways, our goal is to selectively eliminate cancer cells experiencing oxidative stress.
- Exploring the interplay between DNA damage response and immune response in cancer. Our investigations have shed light on the role of the DNA sensor cGAS in triggering the STING-dependent interferon response, subsequently modulating the tumor microenvironment to enhance anti-tumor immunity. Currently, we are examining how DNA damage and R-loops regulate the functions of cGAS in cancer cells. Through our mechanistic studies, we aim to provide a molecular basis for enhancing immune checkpoint blockade-mediated therapy by modulating specific cGAS functions in combination with RDDR targeted therapy.
Overall, the research conducted by the Lan Lab strives to advance our understanding of DNA repair processes in cancer and the role of RNA and R-loops in these processes. We are dedicated to translating our findings into innovative therapeutic strategies that have the potential to revolutionize cancer treatment and improve patient outcomes.
Ann Marie Pendergast
Research Overview:
Tyrosine Kinase-regulated Transcription Networks in tumor progression to metastasis and the regeneration response to injury.
The long-term goal of our research is to define the role of protein tyrosine kinase-regulated transcription networks in the regulation of cell polarity, growth, survival, differentiation, adhesion, and migration during cancer metastasis and the response to tissue injury. We have a long-standing research interest on the role of protein tyrosine phosphorylation in tumorigenesis. Our early research led to seminal discoveries that defined the critical pathways employed by the BCR-ABL tyrosine kinase to induce human leukemia. We employ animal models and state-of-the art transcriptomic technologies to investigate the role of tyrosine kinase-dependent transcription factor networks during tumor metastasis as well as the regeneration response following lung injury. In particular, we are dissecting the pathways that modulate the crosstalk among multiple cell types during metastasis to the brain. Brain metastases represent the most common adult intracranial malignancy with more than 200,000 patients diagnosed in the U.S. annually. Approximately, 20 to 40% of patients with solid tumors will develop brain metastases and lung cancer patients exhibit the highest prevalence of brain metastasis (40-60%) among all cancer types. Current therapies to treat brain metastases have proven ineffective due to variable, transient and incomplete responses, as well as inability for drugs to cross the blood-brain-barrier (BBB) to reach therapeutic doses to treat brain metastasis. We have recently reported that ABL tyrosine kinase-driven transcriptional networks promote brain metastasis in mouse models, and found that treatment with ABL allosteric inhibitors impairs brain metastasis in pre-clinical models. Among the research areas currently being pursued in our laboratory are defining the mechanisms that regulate the cross-talk between brain metastatic cells and associated cells in the brain tumor microenvironment. High-level expression of ABL1, ABL2 and a subset of ABL-dependent target genes correlates with shortened survival of lung adenocarcinoma patients. Thus, ABL-specific allosteric inhibitors might be effective to treat metastatic lung cancer with an activated ABL pathway signature. The ultimate goal of our studies is to develop novel therapies for the treatment of metastatic solid tumors by targeting not only cancer cells but also associated stromal cells in the tumor microenvironment.
Repair following injury requires dynamic intercellular signaling to promote the proper balance of proliferation and differentiation of specialized epithelial progenitor cell populations required to restore normal lung epithelial architecture and barrier function. Absence or imbalance of these processes may result in death or long-term pulmonary disease among survivors. Currently little is known regarding the identity of signaling networks that might be effectively targeted to promote recovery from lung injury. Unexpectedly we found that inhibition of the ABL kinases promotes lung epithelial regeneration in mice after bacterial pneumonia challenge. Further, pathogen exposure elicits a dramatic increase in Abl1 expression in bronchial epithelial cells. Our exciting data demonstrate that inactivation of ABL kinases in mouse models of bacterial and viral pneumonia promotes alveolar epithelial cell regeneration.
Mentoring Philosophy:
My goal is to train the next generation of scientists and leaders by providing essential skills to develop into independent and creative thinkers. I have extensive experience in training and mentoring students, postdoctoral fellows and junior faculty. My laboratory provides a collegial and highly interactive environment to promote collaboration and engagement among lab members and colleagues across the University. We conduct weekly laboratory research and journal club meetings, and weekly one-on-one meetings with trainees to discuss research progress, trouble shooting, planning future research, and writing publications and grants. Lab trainees have gone to successful academic careers and are currently Professors, Associate and Assistant Professors at various academic institutions. I have also trained outstanding post-doctoral fellows who have gone to successful research careers in industry.
Unless otherwise indicated, scholarly articles published by Duke faculty members are made available here with a CC-BY-NC (Creative Commons Attribution Non-Commercial) license, as enabled by the Duke Open Access Policy. If you wish to use the materials in ways not already permitted under CC-BY-NC, please consult the copyright owner. Other materials are made available here through the author’s grant of a non-exclusive license to make their work openly accessible.