Authors
Jing Jin Gu, Kevin M Scott, Arijit Ghosh, Roberto H Barbier, Douglas C Rouse, Jacob P Hoj, Michael W Caminear, Fengqi Zhang, Boya Gao, Margaret W Barbier, Lee Zou, Li Lan, Ann Marie Pendergast
Published in
Cell reports. Volume 45. Issue 7. Pages 117699. Jul 15, 2026. Epub Jul 15, 2026.
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.
PMID:
42461725
Bibliographic data and abstract were imported from PubMed on 17 Jul 2026.
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