ABL Kinase Inactivation Promotes Transcription-Replication Conflicts and Compromises Replication Forks Revealing a Therapeutic Vulnerability in Metastatic Small Cell Lung Cancer

Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine cancer that is typically metastatic upon diagnosis, and has low overall survival. Despite being highly sensitive to first-line chemotherapy or radiotherapy, most patients with SCLC experience relapse and succumb from systemic metastasis. Here we report that inactivation of ABL tyrosine kinases markedly impaired outgrowth of metastatic SCLC tumors in mouse models, resulting in prolonged animal survival. Mechanistically, ABL inactivation in SCLC resulted in increased accumulation of transcription-replication conflicts, compromised replication fork progression, impaired expression and function of proteins implicated in transcription-coupled homologous recombination, and increased DNA damage. Because ABL inactivation increased DNA damage, we evaluated whether blocking the activity DNA damage-repair pathways in the presence of ABL inhibitors might synergize to promote SCLC cell death. We found that co-inactivation of ABL kinase and Ataxia telangiectasia and Rad3-related (ATR), the primary responder of replication stress, synergistically inhibited SCLC cell growth in vitro, and impaired metastatic dissemination and outgrowth compared to single agent treated mice. Thus, combined inactivation of ABL kinase and DNA damage-repair pathways might be exploited to block dissemination and outgrowth of SCLC metastases