A framework for identification of actionable cancer genome dependencies in small cell lung cancer

Martin L. Sos, Felix Dietlein, Martin Peifer, Jakob Schoẗtle, Hyatt Balke-Want, Christian Mul̈ler, Mirjam Koker, André Richters, Stefanie Heynck, Florian Malchers, Johannes M. Heuckmann, Danila Seidel, Patrick A. Eyers, Roland T. Ullrich, Andrey P. Antonchick, Viktor V. Vintonyak, Peter M. Schneider, Takashi Ninomiya, Herbert Waldmann, Reinhard BuẗtnerDaniel Rauh, Lukas C. Heukamp, Roman K. Thomas

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Abstract

Small cell lung cancer (SCLC) accounts for about 15% of all lung cancers. The prognosis of SCLC patients is devastating and no biologically targeted therapeutics are active in this tumor type. To develop a framework for development of specific SCLC-targeted drugs we conducted a combined genomic and pharmacological vulnerability screen in SCLC cell lines. We show that SCLC cell lines capture the genomic landscape of primary SCLC tumors and provide genetic predictors for activity of clinically relevant inhibitors by screening 267 compounds across 44 of these cell lines. We show Aurora kinase inhibitors are effective in SCLC cell lines bearing MYC amplification, which occur in 3-7% of SCLC patients. In MYC-amplified SCLC cells Aurora kinase inhibition associates with G2/M-arrest, inactivation of PI3-kinase (PI3K) signaling, and induction of apoptosis. Aurora dependency in SCLC primarily involved Aurora B, required its kinase activity, and was independent of depletion of cytoplasmic levels of MYC. Our study suggests that a fraction of SCLC patients may benefit from therapeutic inhibition of Aurora B. Thus, thorough chemical and genomic exploration of SCLC cell lines may provide starting points for further development of rational targeted therapeutic intervention in this deadly tumor type.

Original languageEnglish
Pages (from-to)17034-17039
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number42
DOIs
Publication statusPublished - Oct 16 2012

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Small Cell Lung Carcinoma
Genome
Neoplasms
Cell Line
Aurora Kinases
Phosphatidylinositol 3-Kinases
Lung Neoplasms
Phosphotransferases
Therapeutics
Pharmacology
Apoptosis

ASJC Scopus subject areas

  • General

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A framework for identification of actionable cancer genome dependencies in small cell lung cancer. / Sos, Martin L.; Dietlein, Felix; Peifer, Martin; Schoẗtle, Jakob; Balke-Want, Hyatt; Mul̈ler, Christian; Koker, Mirjam; Richters, André; Heynck, Stefanie; Malchers, Florian; Heuckmann, Johannes M.; Seidel, Danila; Eyers, Patrick A.; Ullrich, Roland T.; Antonchick, Andrey P.; Vintonyak, Viktor V.; Schneider, Peter M.; Ninomiya, Takashi; Waldmann, Herbert; Buẗtner, Reinhard; Rauh, Daniel; Heukamp, Lukas C.; Thomas, Roman K.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 42, 16.10.2012, p. 17034-17039.

Research output: Contribution to journalArticle

Sos, ML, Dietlein, F, Peifer, M, Schoẗtle, J, Balke-Want, H, Mul̈ler, C, Koker, M, Richters, A, Heynck, S, Malchers, F, Heuckmann, JM, Seidel, D, Eyers, PA, Ullrich, RT, Antonchick, AP, Vintonyak, VV, Schneider, PM, Ninomiya, T, Waldmann, H, Buẗtner, R, Rauh, D, Heukamp, LC & Thomas, RK 2012, 'A framework for identification of actionable cancer genome dependencies in small cell lung cancer', Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 42, pp. 17034-17039. https://doi.org/10.1073/pnas.1207310109
Sos, Martin L. ; Dietlein, Felix ; Peifer, Martin ; Schoẗtle, Jakob ; Balke-Want, Hyatt ; Mul̈ler, Christian ; Koker, Mirjam ; Richters, André ; Heynck, Stefanie ; Malchers, Florian ; Heuckmann, Johannes M. ; Seidel, Danila ; Eyers, Patrick A. ; Ullrich, Roland T. ; Antonchick, Andrey P. ; Vintonyak, Viktor V. ; Schneider, Peter M. ; Ninomiya, Takashi ; Waldmann, Herbert ; Buẗtner, Reinhard ; Rauh, Daniel ; Heukamp, Lukas C. ; Thomas, Roman K. / A framework for identification of actionable cancer genome dependencies in small cell lung cancer. In: Proceedings of the National Academy of Sciences of the United States of America. 2012 ; Vol. 109, No. 42. pp. 17034-17039.
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N2 - Small cell lung cancer (SCLC) accounts for about 15% of all lung cancers. The prognosis of SCLC patients is devastating and no biologically targeted therapeutics are active in this tumor type. To develop a framework for development of specific SCLC-targeted drugs we conducted a combined genomic and pharmacological vulnerability screen in SCLC cell lines. We show that SCLC cell lines capture the genomic landscape of primary SCLC tumors and provide genetic predictors for activity of clinically relevant inhibitors by screening 267 compounds across 44 of these cell lines. We show Aurora kinase inhibitors are effective in SCLC cell lines bearing MYC amplification, which occur in 3-7% of SCLC patients. In MYC-amplified SCLC cells Aurora kinase inhibition associates with G2/M-arrest, inactivation of PI3-kinase (PI3K) signaling, and induction of apoptosis. Aurora dependency in SCLC primarily involved Aurora B, required its kinase activity, and was independent of depletion of cytoplasmic levels of MYC. Our study suggests that a fraction of SCLC patients may benefit from therapeutic inhibition of Aurora B. Thus, thorough chemical and genomic exploration of SCLC cell lines may provide starting points for further development of rational targeted therapeutic intervention in this deadly tumor type.

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