美国德克萨斯大学MD安德森癌症中心Lauren Averett Byers团队的最新研究发现，转录因子程序和免疫途径激活模式揭示了四种具有不同治疗脆弱性的小细胞肺癌（SCLC）亚型。相关论文在线发表在2021年1月21日出版的《癌细胞》杂志上。

利用肿瘤表达数据和非负矩阵分解，研究人员确定了差异表达转录因子ASCL1、NEUROD1和POU2F3或同时低表达这三个转录因子且表达炎症基因的四种主要SCLC亚型（SCLC-A 、N、P和I）。通过在化疗过程中附加免疫疗法，SCLC-I会获得最大治疗效果，而其他亚型均具有不同的脆弱性，包括对PARP、Aurora激酶或BCL-2抑制剂敏感。

对SCLC-A患者来源的异种移植物进行顺铂治疗会诱导肿瘤向SCLC-I转移，这表明亚型转换是获得性顺铂耐药的原因。研究人员建议应根据肿瘤亚型来匹配相应治疗，以及在治疗中控制亚型转换，可能会增加SCLC患者对治疗的反应深度和持续时间。

研究人员表示，尽管在分子和临床上存在异质性， SCLC被认为是难治性实体瘤。

附：英文原文

Title: Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities

Author: Carl M. Gay, C. Allison Stewart, Elizabeth M. Park, Lixia Diao, Sarah M. Groves, Simon Heeke, Barzin Y. Nabet, Junya Fujimoto, Luisa M. Solis, Wei Lu, Yuanxin Xi, Robert J. Cardnell, Qi Wang, Giulia Fabbri, Kasey R. Cargill, Natalie I. Vokes, Kavya Ramkumar, Bingnan Zhang, Carminia M. Della Corte, Paul Robson, Stephen G. Swisher, Jack A. Roth, Bonnie S. Glisson, David S. Shames, Ignacio I. Wistuba, Jing Wang, Vito Quaranta, John Minna, John V. Heymach, Lauren Averett Byers

Issue&Volume: 2021-01-21

Abstract: Despite molecular and clinical heterogeneity, small cell lung cancer (SCLC) is treatedas a single entity with predictably poor results. Using tumor expression data andnon-negative matrix factorization, we identify four SCLC subtypes defined largelyby differential expression of transcription factors ASCL1, NEUROD1, and POU2F3 orlow expression of all three transcription factor signatures accompanied by an Inflamed gene signature (SCLC-A, N, P, and I, respectively). SCLC-I experiences thegreatest benefit from the addition of immunotherapy to chemotherapy, while the othersubtypes each have distinct vulnerabilities, including to inhibitors of PARP, Aurorakinases, or BCL-2. Cisplatin treatment of SCLC-A patient-derived xenografts inducesintratumoral shifts toward SCLC-I, supporting subtype switching as a mechanism ofacquired platinum resistance. We propose that matching baseline tumor subtype to therapy,as well as manipulating subtype switching on therapy, may enhance depth and durationof response for SCLC patients.

DOI: 10.1016/j.ccell.2020.12.014

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(20)30662-0