MYC Drives Progression of Small Cell Lung Cancer to a Variant Neuroendocrine Subtype with Vulnerability to Aurora Kinase Inhibition

Gurkan Mollaoglu; Matthew R. Guthrie; Stefanie Böhm; Johannes Brägelmann; Ismail Can; Paul M. Ballieu; Annika Marx; Julie George; Christine Heinen; Milind D. Chalishazar; Haixia Cheng; Abbie S. Ireland; Kendall E. Denning; Anandaroop Mukhopadhyay; Jeffery M. Vahrenkamp; Kristofer C. Berrett; Timothy L. Mosbruger; Jun Wang; Jessica L. Kohan; Mohamed E. Salama; Benjamin L. Witt; Martin Peifer; Roman K. Thomas; Jason Gertz; Jane E. Johnson; Adi F. Gazdar; Robert J. Wechsler-Reya; Martin L. Sos; Trudy G. Oliver

doi:10.1016/j.ccell.2016.12.005

MYC Drives Progression of Small Cell Lung Cancer to a Variant Neuroendocrine Subtype with Vulnerability to Aurora Kinase Inhibition

Gurkan Mollaoglu, Matthew R. Guthrie, Stefanie Böhm, Johannes Brägelmann, Ismail Can, Paul M. Ballieu, Annika Marx, Julie George, Christine Heinen, Milind D. Chalishazar, Haixia Cheng, Abbie S. Ireland, Kendall E. Denning, Anandaroop Mukhopadhyay, Jeffery M. Vahrenkamp, Kristofer C. Berrett, Timothy L. Mosbruger, Jun Wang, Jessica L. Kohan, Mohamed E. SalamaBenjamin L. Witt, Martin Peifer, Roman K. Thomas, Jason Gertz, Jane E. Johnson, Adi F. Gazdar, Robert J. Wechsler-Reya, Martin L. Sos, Trudy G. Oliver

Laboratory Medicine and Pathology

Research output: Contribution to journal › Article › peer-review

165 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	270-285
Number of pages	16
Journal	Cancer cell
Volume	31
Issue number	2
DOIs	https://doi.org/10.1016/j.ccell.2016.12.005
State	Published - Feb 13 2017

Keywords

ASCL1
Aurora kinase inhibitor
MYC
NEUROD1
chemotherapy
genetically engineered mouse model
neuroendocrine
small-cell lung cancer

ASJC Scopus subject areas

Oncology
Cancer Research

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Mollaoglu, G., Guthrie, M. R., Böhm, S., Brägelmann, J., Can, I., Ballieu, P. M., Marx, A., George, J., Heinen, C., Chalishazar, M. D., Cheng, H., Ireland, A. S., Denning, K. E., Mukhopadhyay, A., Vahrenkamp, J. M., Berrett, K. C., Mosbruger, T. L., Wang, J., Kohan, J. L., ... Oliver, T. G. (2017). MYC Drives Progression of Small Cell Lung Cancer to a Variant Neuroendocrine Subtype with Vulnerability to Aurora Kinase Inhibition. Cancer cell, 31(2), 270-285. https://doi.org/10.1016/j.ccell.2016.12.005

Mollaoglu, G, Guthrie, MR, Böhm, S, Brägelmann, J, Can, I, Ballieu, PM, Marx, A, George, J, Heinen, C, Chalishazar, MD, Cheng, H, Ireland, AS, Denning, KE, Mukhopadhyay, A, Vahrenkamp, JM, Berrett, KC, Mosbruger, TL, Wang, J, Kohan, JL, Salama, ME, Witt, BL, Peifer, M, Thomas, RK, Gertz, J, Johnson, JE, Gazdar, AF, Wechsler-Reya, RJ, Sos, ML & Oliver, TG 2017, 'MYC Drives Progression of Small Cell Lung Cancer to a Variant Neuroendocrine Subtype with Vulnerability to Aurora Kinase Inhibition', Cancer cell, vol. 31, no. 2, pp. 270-285. https://doi.org/10.1016/j.ccell.2016.12.005

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title = "MYC Drives Progression of Small Cell Lung Cancer to a Variant Neuroendocrine Subtype with Vulnerability to Aurora Kinase Inhibition",

abstract = "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.",

keywords = "ASCL1, Aurora kinase inhibitor, MYC, NEUROD1, chemotherapy, genetically engineered mouse model, neuroendocrine, small-cell lung cancer",

author = "Gurkan Mollaoglu and Guthrie, {Matthew R.} and Stefanie B{\"o}hm and Johannes Br{\"a}gelmann and Ismail Can and Ballieu, {Paul M.} and Annika Marx and Julie George and Christine Heinen and Chalishazar, {Milind D.} and Haixia Cheng and Ireland, {Abbie S.} and Denning, {Kendall E.} and Anandaroop Mukhopadhyay and Vahrenkamp, {Jeffery M.} and Berrett, {Kristofer C.} and Mosbruger, {Timothy L.} and Jun Wang and Kohan, {Jessica L.} and Salama, {Mohamed E.} and Witt, {Benjamin L.} and Martin Peifer and Thomas, {Roman K.} and Jason Gertz and Johnson, {Jane E.} and Gazdar, {Adi F.} and Wechsler-Reya, {Robert J.} and Sos, {Martin L.} and Oliver, {Trudy G.}",

note = "Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",

year = "2017",

month = feb,

day = "13",

doi = "10.1016/j.ccell.2016.12.005",

language = "English (US)",

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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.

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

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KW - genetically engineered mouse model

KW - neuroendocrine

KW - small-cell lung cancer

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MYC Drives Progression of Small Cell Lung Cancer to a Variant Neuroendocrine Subtype with Vulnerability to Aurora Kinase Inhibition

Abstract

Keywords

ASJC Scopus subject areas

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