Document Detail


A framework for identification of actionable cancer genome dependencies in small cell lung cancer.
MedLine Citation:
PMID:  23035247     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Martin L Sos; Felix Dietlein; Martin Peifer; Jakob Schöttle; Hyatt Balke-Want; Christian Müller; 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 Büttner; Daniel Rauh; Lukas C Heukamp; Roman K Thomas
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-10-03
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  109     ISSN:  1091-6490     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-10-17     Completed Date:  2012-12-31     Revised Date:  2013-07-11    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  17034-9     Citation Subset:  IM    
Affiliation:
Department of Translational Genomics, University of Cologne, 50931 Cologne, Germany. martin.sos@ucsf.edu
Data Bank Information
Bank Name/Acc. No.:
GEO/GSE40142
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MeSH Terms
Descriptor/Qualifier:
Apoptosis / drug effects
Cell Line, Tumor
Cell Survival / drug effects
DNA Primers / genetics
Enzyme Inhibitors / pharmacology*
Flow Cytometry
G2 Phase Cell Cycle Checkpoints / drug effects,  physiology*
Humans
Immunoblotting
Organic Chemicals
Phosphatidylinositol 3-Kinases / antagonists & inhibitors
Protein-Serine-Threonine Kinases / antagonists & inhibitors*
Proto-Oncogene Proteins c-myc / metabolism
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction / drug effects*
Small Cell Lung Carcinoma / drug therapy*,  genetics*
Grant Support
ID/Acronym/Agency:
//Howard Hughes Medical Institute
Chemical
Reg. No./Substance:
0/DNA Primers; 0/Enzyme Inhibitors; 0/MYC protein, human; 0/Organic Chemicals; 0/Proto-Oncogene Proteins c-myc; 163795-75-3/SYBR Green I; EC 2.7.1.-/Phosphatidylinositol 3-Kinases; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.11.1/aurora kinase
Comments/Corrections

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