title: A framework for identification of actionable cancer genome dependencies in small cell lung cancer.
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.
authors.affiliation: Department of Translational Genomics, University of Cologne, 50931 Cologne, Germany. martin.sos@ucsf.edu
authors.forename: Martin L
authors.initials: ML
authors.lastname: Sos
authors.forename: Felix
authors.initials: F
authors.lastname: Dietlein
authors.forename: Martin
authors.initials: M
authors.lastname: Peifer
authors.forename: Jakob
authors.initials: J
authors.lastname: Schöttle
authors.forename: Hyatt
authors.initials: H
authors.lastname: Balke-Want
authors.forename: Christian
authors.initials: C
authors.lastname: Müller
authors.forename: Mirjam
authors.initials: M
authors.lastname: Koker
authors.forename: André
authors.initials: A
authors.lastname: Richters
authors.forename: Stefanie
authors.initials: S
authors.lastname: Heynck
authors.forename: Florian
authors.initials: F
authors.lastname: Malchers
authors.forename: Johannes M
authors.initials: JM
authors.lastname: Heuckmann
authors.forename: Danila
authors.initials: D
authors.lastname: Seidel
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Eyers
authors.forename: Roland T
authors.initials: RT
authors.lastname: Ullrich
authors.forename: Andrey P
authors.initials: AP
authors.lastname: Antonchick
authors.forename: Viktor V
authors.initials: VV
authors.lastname: Vintonyak
authors.forename: Peter M
authors.initials: PM
authors.lastname: Schneider
authors.forename: Takashi
authors.initials: T
authors.lastname: Ninomiya
authors.forename: Herbert
authors.initials: H
authors.lastname: Waldmann
authors.forename: Reinhard
authors.initials: R
authors.lastname: Büttner
authors.forename: Daniel
authors.initials: D
authors.lastname: Rauh
authors.forename: Lukas C
authors.initials: LC
authors.lastname: Heukamp
authors.forename: Roman K
authors.initials: RK
authors.lastname: Thomas
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D064107:Aurora Kinase B; D064127:Aurora Kinases; D052160:Benzothiazoles; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D017931:DNA Primers / Q000235:genetics; D003959:Diamines; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005434:Flow Cytometry; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D015151:Immunoblotting; D009930:Organic Chemicals; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D011804:Quinolines; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy* / Q000235:genetics*
chemical_list: D052160:Benzothiazoles; D017931:DNA Primers; D003959:Diamines; D004791:Enzyme Inhibitors; C489427:MYC protein, human; D009930:Organic Chemicals; D000081082:Phosphoinositide-3 Kinase Inhibitors; D016271:Proto-Oncogene Proteins c-myc; D011804:Quinolines; C098022:SYBR Green I; C576921:AURKB protein, human; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases