期刊
CANCER CELL
卷 39, 期 3, 页码 346-+出版社
CELL PRESS
DOI: 10.1016/j.ccell.2020.12.014
关键词
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资金
- NIH/NCI [CCSG P30-CA016672, R01 CA-207295, U01 CA-213273, T32 CA009666, R50-CA243698, U01 CA213338, U24 CA213274]
- CPRIT Research Training Program [RP170067]
- University of Texas System and MD Anderson Lung SPORE [5 P50 CA070907]
- Department of Defense [LC170171]
- ASCO Young Investigator Award
- Khalifa Bin Zayed Al Nahyan Foundation
- MD Anderson Sister Institute Network Fund
- Andrew Sabin Family Fellowship
- Abell Hangar Foundation
- MD Anderson Physician Scientist Award
- Hope Foundation SWOG/ITSC Pilot Program
- LUNGevity Foundation Career Development Award
- Jane Ford Petrin Fund
- Rexanna Foundation for Fighting Lung Cancer
Despite the heterogeneity of small cell lung cancer (SCLC), four subtypes have been identified based on tumor expression data, each showing different responses to treatment. SCLC-I subtype benefits the most from immunotherapy, while other subtypes have vulnerabilities to different inhibitors. Matching tumor subtype to therapy and manipulating subtype switching during treatment may enhance response depth and duration for SCLC patients.
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.
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