TY - JOUR
T1 - MYC Drives Progression of Small Cell Lung Cancer to a Variant Neuroendocrine Subtype with Vulnerability to Aurora Kinase Inhibition
AU - Mollaoglu, Gurkan
AU - Guthrie, Matthew R.
AU - Böhm, Stefanie
AU - Brägelmann, Johannes
AU - Can, Ismail
AU - Ballieu, Paul M.
AU - Marx, Annika
AU - George, Julie
AU - Heinen, Christine
AU - Chalishazar, Milind D.
AU - Cheng, Haixia
AU - Ireland, Abbie S.
AU - Denning, Kendall E.
AU - Mukhopadhyay, Anandaroop
AU - Vahrenkamp, Jeffery M.
AU - Berrett, Kristofer C.
AU - Mosbruger, Timothy L.
AU - Wang, Jun
AU - Kohan, Jessica L.
AU - Salama, Mohamed E.
AU - Witt, Benjamin L.
AU - Peifer, Martin
AU - Thomas, Roman K.
AU - Gertz, Jason
AU - Johnson, Jane E.
AU - Gazdar, Adi F.
AU - Wechsler-Reya, Robert J.
AU - Sos, Martin L.
AU - Oliver, Trudy G.
N1 - Funding Information:
Thanks to K. Sutherland and A. Berns for permission to use Cgrp-Cre viruses; for RP mice provided by T. Jacks and A. Berns, RPP mice and RP tissues from D. MacPherson, and RPR2 tissues from J. Sage. We appreciate technical assistance from members of the Oliver Lab including M. Baladi, B. Anderson, and K. Gligorich for histological services, and B. Dalley for bioinformatics support. Thanks to E. Snyder for critical reading of the manuscript. T.G.O. was supported in part by a V Scholar award from The V Foundation for Cancer Research, the American Cancer Society (Research Scholar Award no. RSG-13-300-01-TBG), and the NIH (no. R01CA187457-01). T.G.O. is a Damon Runyon-Rachleff Innovation Awardee and this work is supported by the Damon Runyon Cancer Research Foundation (no. DRR-26-13). A.M. is supported by the Köln Fortune Research Scholar Award and J.E.J. by CPRIT RP140143. M.L.S. was supported by the EFRE initiative (no. LS-1-1-030a to R.K.T. and M.L.S), German Ministry of Science and Education (BMBF) as part of the e:Med program (no. 01ZX1303 to R.K.T., M.P. and no. 01ZX1406 to M.L.S, M.P.), Deutsche Forschungsgemeinschaft (no. TH1386/3-1 to R.K.T and M.L.S.), and received a commercial research grant from Novartis. Funding to R.K.T. was also provided by the German Cancer Aid (Deutsche Krebshilfe, no. 109679), SFB832 (TP6), Deutsche Krebshilfe as part of Oncology Centers of Excellence, EU-Framework program CURELUNG (HEALTH-F2-2010-258677), PerMed.NRW initiative (no. 005-1111-0025), Stand Up To Cancer—American Association of Cancer Research Innovative Research Grant (SU2C-AACR-IR60109), and German Consortium for Translational Cancer Research Joint Funding program. R.K.T. received commercial research grants (AstraZeneca, EOS, Merck KgaA) and honoraria (AstraZeneca, Bayer, NEO New Oncology AG, Boehringer Ingelheim, Clovis Oncology, Daiichi-Sankyo, Eli Lilly, Johnson & Johnson, Merck KgaA, MSD, Puma, Roche, Sanofi). M.P. is a scientific consultant of NEO New Oncology AG.
Funding Information:
Thanks to K. Sutherland and A. Berns for permission to use Cgrp-Cre viruses; for RP mice provided by T. Jacks and A. Berns, RPP mice and RP tissues from D. MacPherson, and RPR2 tissues from J. Sage. We appreciate technical assistance from members of the Oliver Lab including M. Baladi, B. Anderson, and K. Gligorich for histological services, and B. Dalley for bioinformatics support. Thanks to E. Snyder for critical reading of the manuscript. T.G.O. was supported in part by a V Scholar award from The V Foundation for Cancer Research, the American Cancer Society (Research Scholar Award no. RSG-13-300-01-TBG), and the NIH (no. R01CA187457-01). T.G.O. is a Damon Runyon-Rachleff Innovation Awardee and this work is supported by the Damon Runyon Cancer Research Foundation (no. DRR-26-13). A.M. is supported by the K?ln Fortune Research Scholar Award and J.E.J. by CPRIT RP140143. M.L.S. was supported by the EFRE initiative (no. LS-1-1-030a to R.K.T. and M.L.S), German Ministry of Science and Education (BMBF) as part of the e:Med program (no. 01ZX1303 to R.K.T., M.P. and no. 01ZX1406 to M.L.S, M.P.), Deutsche Forschungsgemeinschaft (no. TH1386/3-1 to R.K.T and M.L.S.), and received a commercial research grant from Novartis. Funding to R.K.T. was also provided by the German Cancer Aid (Deutsche Krebshilfe, no. 109679), SFB832 (TP6), Deutsche Krebshilfe as part of Oncology Centers of Excellence, EU-Framework program CURELUNG (HEALTH-F2-2010-258677), PerMed.NRW initiative (no. 005-1111-0025), Stand Up To Cancer?American Association of Cancer Research Innovative Research Grant (SU2C-AACR-IR60109), and German Consortium for Translational Cancer Research Joint Funding program. R.K.T. received commercial research grants (AstraZeneca, EOS, Merck KgaA) and honoraria (AstraZeneca, Bayer, NEO New Oncology AG, Boehringer Ingelheim, Clovis Oncology, Daiichi-Sankyo, Eli Lilly, Johnson & Johnson, Merck KgaA, MSD, Puma, Roche, Sanofi). M.P. is a scientific consultant of NEO New Oncology AG.
Publisher Copyright:
© 2017 Elsevier Inc.
PY - 2017/2/13
Y1 - 2017/2/13
N2 - Loss of the tumor suppressors RB1 and TP53 and MYC amplification are frequent oncogenic events in small cell lung cancer (SCLC). We show that Myc expression cooperates with Rb1 and Trp53 loss in the mouse lung to promote aggressive, highly metastatic tumors, that are initially sensitive to chemotherapy followed by relapse, similar to human SCLC. Importantly, MYC drives a neuroendocrine-low “variant” subset of SCLC with high NEUROD1 expression corresponding to transcriptional profiles of human SCLC. Targeted drug screening reveals that SCLC with high MYC expression is vulnerable to Aurora kinase inhibition, which, combined with chemotherapy, strongly suppresses tumor progression and increases survival. These data identify molecular features for patient stratification and uncover a potential targeted treatment approach for MYC-driven SCLC.
AB - Loss of the tumor suppressors RB1 and TP53 and MYC amplification are frequent oncogenic events in small cell lung cancer (SCLC). We show that Myc expression cooperates with Rb1 and Trp53 loss in the mouse lung to promote aggressive, highly metastatic tumors, that are initially sensitive to chemotherapy followed by relapse, similar to human SCLC. Importantly, MYC drives a neuroendocrine-low “variant” subset of SCLC with high NEUROD1 expression corresponding to transcriptional profiles of human SCLC. Targeted drug screening reveals that SCLC with high MYC expression is vulnerable to Aurora kinase inhibition, which, combined with chemotherapy, strongly suppresses tumor progression and increases survival. These data identify molecular features for patient stratification and uncover a potential targeted treatment approach for MYC-driven SCLC.
KW - ASCL1
KW - Aurora kinase inhibitor
KW - MYC
KW - NEUROD1
KW - chemotherapy
KW - genetically engineered mouse model
KW - neuroendocrine
KW - small-cell lung cancer
UR - http://www.scopus.com/inward/record.url?scp=85009505564&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85009505564&partnerID=8YFLogxK
U2 - 10.1016/j.ccell.2016.12.005
DO - 10.1016/j.ccell.2016.12.005
M3 - Article
C2 - 28089889
AN - SCOPUS:85009505564
SN - 1535-6108
VL - 31
SP - 270
EP - 285
JO - Cancer cell
JF - Cancer cell
IS - 2
ER -