美国国立卫生研究院Anish Thomas等研究人员合作发现，靶向ATR可在具有高复制压力的小细胞肺癌中产生持久的肿瘤消退。该研究于2021年4月12日发表于国际一流学术期刊《癌细胞》。

使用化学遗传学筛选，研究人员发现ATR（ataxia telangiectasia and rad3 related）是复制应激反应的主要激活因子，而拓扑异构酶I（TOP1）是抑制基因组不稳定性的核酶，在小细胞肺癌（ SCLC）中具有协同细胞毒性作用。在概念验证研究中，研究人员将M6620（berzosertib），新的ATR抑制剂和TOP1抑制剂拓扑替康联合用于小细胞神经内分泌癌（SCNC）复发患者。SCLC患者的客观缓解率为36％（9/25），达到了主要疗效终点。

研究人员在铂耐药SCNC患者中观察到持久的肿瘤消退，这种肿瘤通常在复发几周内致命。具有高度神经内分泌分化能力（以复制压力增强为特征）的SCNC更可能做出反应。这些发现突显出复制压力是SCNC潜在的转化靶点，为这些癌症中的患者选择铺平了道路。

据介绍，SCNC是顽固性癌症，由多种主要部位引起，并且缺乏有效的治疗方法。

附：英文原文

Title: Therapeutic targeting of ATR yields durable regressions in small cell lung cancers with high replication stress

Author: 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

Issue&Volume: 2021/04/12

Abstract: Small cell neuroendocrine cancers (SCNCs) are recalcitrant cancers arising from diverseprimary sites that lack effective treatments. Using chemical genetic screens, we identifiedinhibition of ataxia telangiectasia and rad3 related (ATR), the primary activatorof the replication stress response, and topoisomerase I (TOP1), nuclear enzyme thatsuppresses genomic instability, as synergistically cytotoxic in small cell lung cancer(SCLC). In a proof-of-concept study, we combined M6620 (berzosertib), first-in-classATR inhibitor, and TOP1 inhibitor topotecan in patients with relapsed SCNCs. Objectiveresponse rate among patients with SCLC was 36% (9/25), achieving the primary efficacyendpoint. Durable tumor regressions were observed in patients with platinum-resistantSCNCs, typically fatal within weeks of recurrence. SCNCs with high neuroendocrinedifferentiation, characterized by enhanced replication stress, were more likely torespond. These findings highlight replication stress as a potentially transformativevulnerability of SCNCs, paving the way for rational patient selection in these cancers,now treated as a single disease.

DOI: 10.1016/j.ccell.2021.02.014

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(21)00116-1