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

被引：571

作者：

Gay, Carl M. ^{[1
]}

Stewart, C. Allison ^{[1
]}

Park, Elizabeth M. ^{[1
]}

Diao, Lixia ^{[2
]}

Groves, Sarah M. ^{[3
]}

Heeke, Simon ^{[1
]}

Nabet, Barzin Y. ^{[4
]}

Fujimoto, Junya ^{[5
]}

Solis, Luisa M. ^{[5
]}

Lu, Wei ^{[5
]}

Xi, Yuanxin ^{[2
]}

Cardnell, Robert J. ^{[1
]}

Wang, Qi ^{[2
]}

Fabbri, Giulia ^{[6
]}

Cargill, Kasey R. ^{[1
]}

Vokes, Natalie, I ^{[1
]}

Ramkumar, Kavya ^{[1
]}

Zhang, Bingnan ^{[1
]}

Della Corte, Carminia M. ^{[7
]}

Robson, Paul ^{[8
]}

Swisher, Stephen G. ^{[9
]}

Roth, Jack A. ^{[9
]}

Glisson, Bonnie S. ^{[1
]}

Shames, David S. ^{[4
]}

Wistuba, Ignacio I. ^{[5
]}

Wang, Jing ^{[2
]}

Quaranta, Vito ^{[3
]}

Minna, John ^{[10
]}

Heymach, John, V ^{[1
]}

Byers, Lauren Averett ^{[1
]}

机构：

[1] Univ Texas MD Anderson Canc Ctr, Dept Thorac Head & Neck Med Oncol, Houston, TX 77030 USA

[2] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA

[3] Vanderbilt Univ, Dept Biochem, Med Ctr, Nashville, TN USA

[4] Genentech Inc, Dept Oncol Biomarker Dev, San Francisco, CA 94080 USA

[5] Univ Texas MD Anderson Canc Ctr, Dept Translat Mol Pathol, Houston, TX 77030 USA

[6] AstraZeneca, Waltham, MA USA

[7] Univ Campania Luigi Vanvitelli, Dept Precis Med, Oncol Div, Naples, Italy

[8] Jackson Lab Genom Med, Farmington, CT USA

[9] Univ Texas MD Anderson Canc Ctr, Dept Thorac & Cardiovasc Surg, Houston, TX 77030 USA

[10] Univ Texas Southwestern Med Ctr Dallas, Dept Internal Med & Simmons Canc Ctr, Dallas, TX 75390 USA

来源：

CANCER CELL | 2021年 / 39卷 / 03期

关键词：

CELL LUNG-CANCER; ANTIBODY-DRUG CONJUGATE; LABETUZUMAB GOVITECAN; HETEROGENEITY; EXPRESSION; TUMORS; LINES; PEMBROLIZUMAB; INHIBITORS; CISPLATIN;

D O I：

10.1016/j.ccell.2020.12.014

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 amechanism 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.

引用

页码：346 / +

页数：22

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