Sos, Martin L., Dietlein, Felix, Peifer, Martin ORCID: 0000-0002-5243-5503, Schoettle, Jakob, Balke-Want, Hyatt, Mueller, Christian, Koker, Mirjam, Richters, Andre, Heynck, Stefanie, Malchers, Florian, Heuckmann, Johannes M., Seidel, Danila, Eyers, Patrick A., Ullrich, Roland T., Antonchick, Andrey P., Vintonyak, Viktor V., Schneider, Peter M. ORCID: 0000-0003-0744-2349, Ninomiya, Takashi, Waldmann, Herbert ORCID: 0000-0002-9606-7247, Buettner, Reinhard, Rauh, Daniel ORCID: 0000-0002-1970-7642, Heukamp, Lukas C. and Thomas, Roman K. (2012). A framework for identification of actionable cancer genome dependencies in small cell lung cancer. Proc. Natl. Acad. Sci. U. S. A., 109 (42). S. 17034 - 17040. WASHINGTON: NATL ACAD SCIENCES. ISSN 0027-8424

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Sos, Martin L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dietlein, FelixUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peifer, MartinUNSPECIFIEDorcid.org/0000-0002-5243-5503UNSPECIFIED
Schoettle, JakobUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Balke-Want, HyattUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mueller, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koker, MirjamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Richters, AndreUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heynck, StefanieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Malchers, FlorianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heuckmann, Johannes M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Seidel, DanilaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Eyers, Patrick A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ullrich, Roland T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Antonchick, Andrey P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vintonyak, Viktor V.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schneider, Peter M.UNSPECIFIEDorcid.org/0000-0003-0744-2349UNSPECIFIED
Ninomiya, TakashiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Waldmann, HerbertUNSPECIFIEDorcid.org/0000-0002-9606-7247UNSPECIFIED
Buettner, ReinhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rauh, DanielUNSPECIFIEDorcid.org/0000-0002-1970-7642UNSPECIFIED
Heukamp, Lukas C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thomas, Roman K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-480997
DOI: 10.1073/pnas.1207310109
Journal or Publication Title: Proc. Natl. Acad. Sci. U. S. A.
Volume: 109
Number: 42
Page Range: S. 17034 - 17040
Date: 2012
Publisher: NATL ACAD SCIENCES
Place of Publication: WASHINGTON
ISSN: 0027-8424
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
GROWTH-FACTOR RECEPTOR; AURORA-B KINASE; SELECTIVE INHIBITORS; DRUG-SENSITIVITY; MYC; MUTATIONS; GENE; GEFITINIB; EGFR; FAMILYMultiple languages
Multidisciplinary SciencesMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/48099

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