Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 346-360.e7 |
| Journal | Cancer Cell |
| Volume | 39 |
| Issue number | 3 |
| DOIs | |
| State | Published - Mar 8 2021 |
Keywords
- ASCL1
- EMT
- NEUROD1
- POU2F3
- SCLC
- intratumoral heterogeneity
- neuroendocrine
ASJC Scopus subject areas
- Oncology
- Cell Biology
- Cancer Research
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Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities. / Gay, Carl M.; Stewart, C. Allison; Park, Elizabeth M. et al.
In: Cancer Cell, Vol. 39, No. 3, 08.03.2021, p. 346-360.e7.Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities
AU - Gay, Carl M.
AU - Stewart, C. Allison
AU - Park, Elizabeth M.
AU - Diao, Lixia
AU - Groves, Sarah M.
AU - Heeke, Simon
AU - Nabet, Barzin Y.
AU - Fujimoto, Junya
AU - Solis, Luisa M.
AU - Lu, Wei
AU - Xi, Yuanxin
AU - Cardnell, Robert J.
AU - Wang, Qi
AU - Fabbri, Giulia
AU - Cargill, Kasey R.
AU - Vokes, Natalie I.
AU - Ramkumar, Kavya
AU - Zhang, Bingnan
AU - Della Corte, Carminia M.
AU - Robson, Paul
AU - Swisher, Stephen G.
AU - Roth, Jack A.
AU - Glisson, Bonnie S.
AU - Shames, David S.
AU - Wistuba, Ignacio I.
AU - Wang, Jing
AU - Quaranta, Vito
AU - Minna, John
AU - Heymach, John V.
AU - Byers, Lauren Averett
N1 - Funding Information: We are grateful to all of the patients who provided blood and tissue samples for this work. We would like to dedicate this work to Dr. Adi Gazdar who made invaluable intellectual contributions to this study prior to his passing. We thank Jordan Pietz for illustrations. This work was supported by: The NIH/NCI CCSG P30-CA016672 (Bioinformatics Shared Resource); NIH/NCI R01 CA-207295 (L.A.B.); NIH/NCI U01 CA-213273 (J.V.H. L.A.B.); NIH/NCI T32 CA009666 (C.M.G.); NIH/NCI R50-CA243698 (C.A.S.); NIH/NCI U01 CA213338 (J.M.); NIH/NCI U24 CA213274 (J.M.); CPRIT Research Training Program (RP170067) (E.M.P.); The University of Texas System and MD Anderson Lung SPORE (5 P50 CA070907) (C.M.G. J.R. I.I.W. J.W. J.M. J.V.H. L.A.B.); The Department of Defense LC170171 (L.A.B.); ASCO Young Investigator Award (C.M.G.); the Khalifa Bin Zayed Al Nahyan Foundation (C.M.G.); MD Anderson Sister Institute Network Fund (L.A.B.); through generous philanthropic contributions to The University of Texas MD Anderson Lung Cancer Moon Shot Program (J.V.H. J.W. L.A.B.); The Andrew Sabin Family Fellowship (L.A.B.); C.M.G. and L.A.B. were supported by the Abell Hangar Foundation (B.S.G.); MD Anderson Physician Scientist Award (L.A.B.); The Hope Foundation SWOG/ITSC Pilot Program (P.R. and L.A.B.); the LUNGevity Foundation Career Development Award (C.M.G.); a generous philanthropic contribution by the Jane Ford Petrin Fund (J.V.H.); and the Rexanna Foundation for Fighting Lung Cancer (C.M.G. J.V.H. L.A.B.). We would also especially like to thank The Knights of Columbus Wimberley TX, A.R.K. L.W.Y. and M.J.A. for their philanthropic support of these projects. C.M.G. C.A.S. E.M.P. L.D. J.V.H. and L.A.B. conceived the project, analyzed and interpreted the data, and wrote the manuscript. J.F. L.M.S. W.L. and I.I.W. performed pathology review and analysis; S.F.M. S.H. B.Y.N. Y.X. R.J.C. Q.W. G.F. K.R.C. N.I.V. K.R. B.Z. C.M.D.C. D.S.S. J.W. and V.Q. contributed to the analysis and interpretation of data. P.R. S.G.S. J.A.R. B.S.G. and J.M. contributed to the acquisition of data, administrative, and/or material support. All authors contributed to the writing, review, and/or revision of the manuscript. C.M.G. reports research funding from AstraZeneca. S.H. reports consulting/honoraria from Qiagen, Boehringer Ingelheim and travel funding from Roche. B.Y.Z. and D.S.S. are employees of Genentech, Inc. G.F. is an employee of AstraZeneca and has stock ownership in AstraZeneca. B.G. reports research funding from ISA Pharm, Cue Bio, Pfizer, and Medimmune. I.I.W. reports consulting/advisory roles for Medscape, MSD, Genentech/Roche, PlatformQ Health, Pfizer, Bayer, Bristol-Myers Squibb, AstraZeneca/Medimmune, HTG Molecular, Asuragen, Merck, GlaxoSmithKline, Guardant Health, Oncocyte, and MSD, research support from Genentech, Oncoplex, HTG Molecular, DepArray, Merck, Bristol-Myers Squibb, Medimmune, Adapative, Adaptimmune, EMD Serono, Pfizer, Takeda, Amgen, Karus, Johnson & Johnson, Bayer, Iovance, 4D, Novartis and Akoya. J.V.H. serves on advisory committees for AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Guardant Health, Kairos Venture Investments, BrightPath Biotherapeutics, Hengrui Therapeutics, Eli Lilly, Spectrum, EMD Serono, Roche, and Foundation One Medicine and has research support from AstraZeneca, Spectrum, and Checkmate Pharmaceuticals, as well as royalties/licensing fees from Spectrum and Bio-Tree Systems. L.A.B. serves on advisory committees for AstraZeneca, AbbVie, GenMab, BergenBio, Pharma Mar SA, Sierra Oncology, Merck, Bristol-Myers Squibb, Genentech, and Pfizer and has research support from AbbVie, AstraZeneca, GenMab, Sierra Oncology, Tolero Pharmaceuticals. C.M.G. L.A.B. and J.V.H. have pending patent applications for SCLC subtyping U.S. 62/895,322. Otherwise, there are no pertinent financial or non-financial conflicts of interest to report. Funding Information: We are grateful to all of the patients who provided blood and tissue samples for this work. We would like to dedicate this work to Dr. Adi Gazdar who made invaluable intellectual contributions to this study prior to his passing. We thank Jordan Pietz for illustrations. This work was supported by: The NIH / NCI CCSG P30-CA016672 (Bioinformatics Shared Resource); NIH/NCI R01 CA-207295 (L.A.B.); NIH/NCI U01 CA-213273 (J.V.H., L.A.B.); NIH /NCI T32 CA009666 (C.M.G.); NIH /NCI R50-CA243698 (C.A.S.); NIH/NCI U01 CA213338 (J.M.); NIH/NCI U24 CA213274 (J.M.); CPRIT Research Training Program ( RP170067 ) (E.M.P.); The University of Texas System and MD Anderson Lung SPORE ( 5 P50 CA070907 ) (C.M.G., J.R., I.I.W., J.W., J.M., J.V.H., L.A.B.); The Department of Defense LC170171 (L.A.B.); ASCO Young Investigator Award (C.M.G.); the Khalifa Bin Zayed Al Nahyan Foundation (C.M.G.); MD Anderson Sister Institute Network Fund (L.A.B.); through generous philanthropic contributions to The University of Texas MD Anderson Lung Cancer Moon Shot Program (J.V.H., J.W., L.A.B.); The Andrew Sabin Family Fellowship (L.A.B.); C.M.G. and L.A.B. were supported by the Abell Hangar Foundation (B.S.G.); MD Anderson Physician Scientist Award (L.A.B.); The Hope Foundation SWOG/ITSC Pilot Program (P.R. and L.A.B.); the LUNGevity Foundation Career Development Award (C.M.G.); a generous philanthropic contribution by the Jane Ford Petrin Fund (J.V.H.); and the Rexanna Foundation for Fighting Lung Cancer (C.M.G., J.V.H., L.A.B.). We would also especially like to thank The Knights of Columbus Wimberley TX, A.R.K., L.W.Y., and M.J.A. for their philanthropic support of these projects. Funding Information: C.M.G. reports research funding from AstraZeneca. S.H. reports consulting/honoraria from Qiagen, Boehringer Ingelheim and travel funding from Roche. B.Y.Z. and D.S.S. are employees of Genentech, Inc. G.F. is an employee of AstraZeneca and has stock ownership in AstraZeneca. B.G. reports research funding from ISA Pharm, Cue Bio, Pfizer, and Medimmune. I.I.W. reports consulting/advisory roles for Medscape, MSD, Genentech/Roche, PlatformQ Health, Pfizer, Bayer, Bristol-Myers Squibb, AstraZeneca/Medimmune, HTG Molecular, Asuragen, Merck, GlaxoSmithKline, Guardant Health, Oncocyte, and MSD, research support from Genentech, Oncoplex, HTG Molecular, DepArray, Merck, Bristol-Myers Squibb, Medimmune, Adapative, Adaptimmune, EMD Serono, Pfizer, Takeda, Amgen, Karus, Johnson & Johnson, Bayer, Iovance, 4D, Novartis and Akoya. J.V.H. serves on advisory committees for AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Guardant Health, Kairos Venture Investments, BrightPath Biotherapeutics, Hengrui Therapeutics, Eli Lilly, Spectrum, EMD Serono, Roche, and Foundation One Medicine and has research support from AstraZeneca, Spectrum, and Checkmate Pharmaceuticals, as well as royalties/licensing fees from Spectrum and Bio-Tree Systems. L.A.B. serves on advisory committees for AstraZeneca, AbbVie, GenMab, BergenBio, Pharma Mar SA, Sierra Oncology, Merck, Bristol-Myers Squibb, Genentech, and Pfizer and has research support from AbbVie, AstraZeneca, GenMab, Sierra Oncology, Tolero Pharmaceuticals. C.M.G., L.A.B., and J.V.H. have pending patent applications for SCLC subtyping U.S. 62/895,322. Otherwise, there are no pertinent financial or non-financial conflicts of interest to report. Publisher Copyright: © 2020 Elsevier Inc.
PY - 2021/3/8
Y1 - 2021/3/8
N2 - 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.
AB - 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.
KW - ASCL1
KW - EMT
KW - NEUROD1
KW - POU2F3
KW - SCLC
KW - intratumoral heterogeneity
KW - neuroendocrine
UR - http://www.scopus.com/inward/record.url?scp=85100528860&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85100528860&partnerID=8YFLogxK
U2 - 10.1016/j.ccell.2020.12.014
DO - 10.1016/j.ccell.2020.12.014
M3 - Article
C2 - 33482121
AN - SCOPUS:85100528860
VL - 39
SP - 346-360.e7
JO - Cancer Cell
JF - Cancer Cell
SN - 1535-6108
IS - 3
ER -