作者
Anish Thomas, Nobuyuki Takahashi, Vinodh N Rajapakse, Xiaohu Zhang, Yilun Sun, Michele Ceribelli, Kelli M Wilson, Yang Zhang, Erin Beck, Linda Sciuto, Samantha Nichols, Brian Elenbaas, Janusz Puc, Heike Dahmen, Astrid Zimmermann, Jillian Varonin, Christopher W Schultz, Sehyun Kim, Hirity Shimellis, Parth Desai, Carleen Klumpp-Thomas, Lu Chen, Jameson Travers, Crystal McKnight, Sam Michael, Zina Itkin, Sunmin Lee, Akira Yuno, Min-Jung Lee, Christophe E Redon, Jessica D Kindrick, Cody J Peer, Jun S Wei, Mirit I Aladjem, William Douglas Figg, Seth M Steinberg, Jane B Trepel, Frank T Zenke, Yves Pommier, Javed Khan, Craig J Thomas
发表日期
2021/4/12
期刊
Cancer Cell
卷号
39
期号
4
页码范围
566-579. e7
出版商
Elsevier
简介
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 …
学术搜索中的文章
A Thomas, N Takahashi, VN Rajapakse, X Zhang… - Cancer Cell, 2021