Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities.
Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities.
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DOI：
10.1016/j.ccell.2020.12.014
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发表时间：
2021-03-08
期刊：
影响因子：
50.3
通讯作者：
Byers LA
中科院分区：
文献类型：
--
作者：
Gay CM;Stewart CA;Park EM;Diao L;Groves SM;Heeke S;Nabet BY;Fujimoto J;Solis LM;Lu W;Xi Y;Cardnell RJ;Wang Q;Fabbri G;Cargill KR;Vokes NI;Ramkumar K;Zhang B;Della Corte CM;Robson P;Swisher SG;Roth JA;Glisson BS;Shames DS;Wistuba II;Wang J;Quaranta V;Minna J;Heymach JV;Byers LA
尽管分子和临床异质性，小细胞肺癌（SCLC）被视为一个单一的实体与可预见的穷人的结果。使用肿瘤表达数据和非负矩阵因子分解，我们确定了四种SCLC亚型，主要由转录因子ASCL 1、NEUROD 1和POU 2F 3的差异表达或所有三种转录因子标签的低表达伴随炎症基因标签（分别为SCLC-A、N、P和I）定义。SCLC-I在化疗中加入免疫疗法的获益最大，而其他亚型各自具有不同的脆弱性，包括PARP，Aurora激酶或BCL-2的抑制剂。顺铂治疗SCLC-A患者来源的异种移植物诱导肿瘤内向SCLC-I转变，支持亚型转换作为获得性铂耐药的机制。我们建议将基线肿瘤亚型与治疗相匹配，以及操纵亚型切换治疗，可以增强SCLC患者的反应深度和持续时间。Gay等人提供了四种小细胞肺癌亚型的分类，每种亚型都具有独特的分子特征和治疗弱点。一种发炎的间质亚型预测在化疗的基础上增加免疫治疗的益处。肿瘤内化疗敏感和化疗耐药亚型之间的转换伴随着治疗耐药性。
Despite molecular and clinical heterogeneity, small cell lung cancer (SCLC) is treated as a single entity with predictably poor results. Using tumor expression data and non-negative matrix factorization, we identify four SCLC subtypes defined largely by differential expression of transcription factors ASCL1, NEUROD1, and POU2F3 or low expression of all three transcription factor signatures accompanied by an Inflamed gene signature (SCLC-A, N, P and I, respectively). SCLC-I experiences the greatest benefit from the addition of immunotherapy to chemotherapy, while the other subtypes each have distinct vulnerabilities, including to inhibitors of PARP, Aurora kinases, or BCL-2. Cisplatin treatment of SCLC-A patient-derived xenografts induces intratumoral shifts toward SCLC-I, supporting subtype switching as a mechanism of acquired platinum resistance. We propose that matching baseline tumor subtype to therapy, as well as manipulating subtype switching on therapy, may enhance depth and duration of response for SCLC patients. Gay et al. provide a classification for four subtypes of small cell lung cancer, each with unique molecular features and therapeutic vulnerabilities. An inflamed, mesenchymal subtype predicts benefit with the addition of immunotherapy to chemotherapy. Intratumoral switching between chemosensitive and chemoresistant subtypes accompanies therapeutic resistance.
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影响因子：
8.8
作者：
Borromeo MD;Savage TK;Kollipara RK;He M;Augustyn A;Osborne JK;Girard L;Minna JD;Gazdar AF;Cobb MH;Johnson JE
通讯作者：
Johnson JE
影响因子：
50.3
作者：
Hellmann MD;Callahan MK;Awad MM;Calvo E;Ascierto PA;Atmaca A;Rizvi NA;Hirsch FR;Selvaggi G;Szustakowski JD;Sasson A;Golhar R;Vitazka P;Chang H;Geese WJ;Antonia SJ
通讯作者：
Antonia SJ
影响因子：
6.2
作者：
Byers LA;Rudin CM
通讯作者：
Rudin CM
影响因子：
28.2
作者：
Kitajima S;Ivanova E;Guo S;Yoshida R;Campisi M;Sundararaman SK;Tange S;Mitsuishi Y;Thai TC;Masuda S;Piel BP;Sholl LM;Kirschmeier PT;Paweletz CP;Watanabe H;Yajima M;Barbie DA
通讯作者：
Barbie DA
影响因子：
10.9
作者：
Bonnafous C;Peri V;Trichard S;Perrot I;Cornen S;Thielens A;Breso V;Morel Y;Rossi B;Paturel C;Gauthier L;Bléry M
通讯作者：
Bléry M