ABL激酶失活在转移性小细胞肺癌中诱导转录-复制冲突并损害复制分支进展
ABL kinase inactivation induces transcription-replication conflicts and impairs replication fork progression in metastatic small cell lung cancer.
摘要(中文译文)
小细胞肺癌（SCLC）是一种高度侵袭性的神经内分泌肿瘤，通常在确诊时已发生转移，总生存期较差。在此我们报道，ABL酪氨酸激酶的失活可抑制转移性SCLC肿瘤的生长，从而延长动物生存期。ABL失活增加了转录-复制冲突（TRCs）的积累，损害了复制叉的推进，并影响了参与转录偶联同源重组的相关蛋白功能，包括RAD51和RAD52。在机制上，ABL介导的RAD52和RAD51酪氨酸磷酸化分别阻止了TRCs的积累和促进了复制叉的推进。由于ABL失活增加了DNA损伤，我们评估了在ABL抑制剂存在的情况下阻断DNA损伤修复通路活性是否可能协同促进SCLC细胞死亡。同时失活ABL和ATR（复制应激的主要应答因子）可在体外协同抑制SCLC细胞生长，并较单药治疗小鼠更显著地抑制转移性生长。因此，ABL与DNA损伤修复通路的共同失活或可用于抑制SCLC转移灶的生长。
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.
如何引用
AMA
Jing Jin Gu, Kevin M Scott, Arijit Ghosh, Roberto H Barbier, Douglas C Rouse, Jacob P Hoj, et al. ABL kinase inactivation induces transcription-replication conflicts and impairs replication fork progression in metastatic small cell lung cancer.. Cell reports. 2026; doi:10.1016/j.celrep.2026.117699.
APA
Jing Jin Gu, Kevin M Scott, Arijit Ghosh, Roberto H Barbier, Douglas C Rouse, Jacob P Hoj, et al (2026). ABL kinase inactivation induces transcription-replication conflicts and impairs replication fork progression in metastatic small cell lung cancer.. Cell reports. https://doi.org/10.1016/j.celrep.2026.117699
GB/T 7714
Jing Jin Gu, Kevin M Scott, Arijit Ghosh, Roberto H Barbier, Douglas C Rouse, Jacob P Hoj, et al. ABL kinase inactivation induces transcription-replication conflicts and impairs replication fork progression in metastatic small cell lung cancer.[J]. Cell reports, 2026 doi:10.1016/j.celrep.2026.117699.
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