Therapeutic targeting of ATR yields durable regressions in small cell lung cancers with high replication stress.
Therapeutic targeting of ATR yields durable regressions in small cell lung cancers with high replication stress.
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DOI：
10.1016/j.ccell.2021.02.014
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发表时间：
2021-04-12
期刊：
影响因子：
50.3
通讯作者：
Thomas CJ
中科院分区：
文献类型：
--
作者：
Thomas A;Takahashi N;Rajapakse VN;Zhang X;Sun Y;Ceribelli M;Wilson KM;Zhang Y;Beck E;Sciuto L;Nichols S;Elenbaas B;Puc J;Dahmen H;Zimmermann A;Varonin J;Schultz CW;Kim S;Shimellis H;Desai P;Klumpp-Thomas C;Chen L;Travers J;McKnight C;Michael S;Itkin Z;Lee S;Yuno A;Lee MJ;Redon CE;Kindrick JD;Peer CJ;Wei JS;Aladjem MI;Figg WD;Steinberg SM;Trepel JB;Zenke FT;Pommier Y;Khan J;Thomas CJ
小细胞神经内分泌癌（SCNC）是由缺乏有效治疗的不同原发部位引起的恶性肿瘤。使用化学遗传筛选，我们确定抑制共济失调毛细血管扩张和Rad 3相关（ATR），复制应激反应的主要激活剂，和拓扑异构酶I（TOP 1），抑制基因组不稳定性的核酶，作为协同细胞毒性在小细胞肺癌（SCLC）。在一项概念验证研究中，我们将M6620（berzosertib），一类ATR抑制剂和TOP 1抑制剂拓扑替康联合治疗复发性SCNC患者。SCLC患者的客观缓解率为36%（9/25），达到主要疗效终点。在铂类耐药SCNC患者中观察到持久的肿瘤消退，通常在复发数周内致命。具有高神经内分泌分化的SCNC，其特征在于增强的复制应激，更有可能作出反应。这些发现强调了复制应激作为一种潜在的变革性治疗SCNC脆弱性，为这些癌症的合理患者选择铺平了道路，现在作为一种单一的疾病进行治疗。托马斯等人将DNA复制应激确定为小细胞神经内分泌癌（SCNC）的治疗脆弱性。具有高神经内分泌和增强复制应激的SCNC更可能对ATR和拓扑异构酶1抑制反应，这在铂耐药肿瘤患者中产生持久的肿瘤消退。
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), 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 therapeutic SCNC vulnerability, paving the way for rational patient selection in these cancers, now treated as a single disease. Thomas et al identify DNA replication stress as a therapeutic vulnerability of small cell neuroendocrine cancers (SCNCs). SCNCs with high neuroendocrine and enhanced replication stress are more likely to respond to ATR and topoisomerase 1 inhibition, which yielded durable tumor regressions in patients with platinum-resistant tumors.
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影响因子：
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