期刊
CANCER CELL
卷 39, 期 4, 页码 566-+出版社
CELL PRESS
DOI: 10.1016/j.ccell.2021.02.014
关键词
-
资金
- Center for Cancer Research, National Cancer Institute [ZIA BC 011793]
- Division of Preclinical Innovation, National Center for Advancing Translational Sciences of the NIH
Inhibiting ATR, the primary activator of replication stress, and TOP1, which suppresses genomic instability, synergistically showed cytotoxic effects in small cell lung cancer. The combination of ATR inhibitor M6620 and TOP1 inhibitor topotecan achieved a 36% objective response rate in SCLC patients, with durable tumor regressions observed in platinum-resistant SCNCs. These findings suggest that replication stress may be a transformative vulnerability in SCNCs, allowing for rational patient selection and potential personalized treatment strategies.
Small cell neuroendocrine cancers (SCNCs) are recalcitrant cancers arising from diverse primary sites that lack effective treatments. Using chemical genetic screens, we identified inhibition of ataxia telangiectasia and rad3 related (ATR), the primary activator of the replication stress response, and topoisomerase I (TOP1), nuclear enzyme that suppresses genomic instability, as synergistically cytotoxic in small cell lung cancer (SCLC). In a proof-of-concept study, we combined M6620 (berzosertib), first-in-class ATR inhibitor, and TOP1 inhibitor topotecan in patients with relapsed SCNCs. Objective response rate among patients with SCLC was 36% (9/25), achieving the primary efficacy endpoint. Durable tumor regressions were observed in patients with platinum-resistant SCNCs, typically fatal within weeks of recurrence. SCNCs with high neuroendocrine differentiation, characterized by enhanced replication stress, were more likely to respond. These findings highlight replication stress as a potentially transformative vulnerability of SCNCs, paving the way for rational patient selection in these cancers, now treated as a single disease.
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