title: Predicting drug susceptibility of non-small cell lung cancers based on genetic lesions.
abstract: Somatic genetic alterations in cancers have been linked with response to targeted therapeutics by creation of specific dependency on activated oncogenic signaling pathways. However, no tools currently exist to systematically connect such genetic lesions to therapeutic vulnerability. We have therefore developed a genomics approach to identify lesions associated with therapeutically relevant oncogene dependency. Using integrated genomic profiling, we have demonstrated that the genomes of a large panel of human non-small cell lung cancer (NSCLC) cell lines are highly representative of those of primary NSCLC tumors. Using cell-based compound screening coupled with diverse computational approaches to integrate orthogonal genomic and biochemical data sets, we identified molecular and genomic predictors of therapeutic response to clinically relevant compounds. Using this approach, we showed that v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations confer enhanced Hsp90 dependency and validated this finding in mice with KRAS-driven lung adenocarcinoma, as these mice exhibited dramatic tumor regression when treated with an Hsp90 inhibitor. In addition, we found that cells with copy number enhancement of v-abl Abelson murine leukemia viral oncogene homolog 2 (ABL2) and ephrin receptor kinase and v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (avian) (SRC) kinase family genes were exquisitely sensitive to treatment with the SRC/ABL inhibitor dasatinib, both in vitro and when it xenografted into mice. Thus, genomically annotated cell-line collections may help translate cancer genomics information into clinical practice by defining critical pathway dependencies amenable to therapeutic inhibition.
authors.affiliation: Max Planck Institute for Neurological Research, Klaus-Joachim-Zülch Laboratories of Max Planck Society, and University of Köln Medical Faculty, University of Köln, Cologne, Germany.
authors.forename: Martin L
authors.initials: ML
authors.lastname: Sos
authors.forename: Kathrin
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authors.lastname: Michel
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authors.lastname: Zander
authors.forename: Jonathan
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authors.lastname: Weiss
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authors.lastname: Rauh
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authors.lastname: Mermel
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authors.lastname: Beroukhim
authors.forename: William
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authors.lastname: Winckler
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authors.forename: Whei F
authors.initials: WF
authors.lastname: Moriarty
authors.forename: Megan
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authors.lastname: Hanna
authors.forename: Laura
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authors.lastname: Tolosi
authors.forename: Jörg
authors.initials: J
authors.lastname: Rahnenführer
authors.forename: Roel
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authors.lastname: Verhaak
authors.forename: Derek
authors.initials: D
authors.lastname: Chiang
authors.forename: Gad
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authors.lastname: Getz
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authors.lastname: Hellmich
authors.forename: Jürgen
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authors.lastname: Girard
authors.forename: Michael
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authors.lastname: Peyton
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Weir
authors.forename: Tzu-Hsiu
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authors.lastname: Chen
authors.forename: Heidi
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authors.lastname: Greulich
authors.forename: Jordi
authors.initials: J
authors.lastname: Barretina
authors.forename: Geoffrey I
authors.initials: GI
authors.lastname: Shapiro
authors.forename: Levi A
authors.initials: LA
authors.lastname: Garraway
authors.forename: Adi F
authors.initials: AF
authors.lastname: Gazdar
authors.forename: John D
authors.initials: JD
authors.lastname: Minna
authors.forename: Matthew
authors.initials: M
authors.lastname: Meyerson
authors.forename: Kwok-Kin
authors.initials: KK
authors.lastname: Wong
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mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D066246:ErbB Receptors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D008279:Magnetic Resonance Imaging; D051379:Mice; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D017434:Protein Structure, Tertiary; D013379:Substrate Specificity
chemical_list: D000970:Antineoplastic Agents; D066246:ErbB Receptors