Systematically linking drug susceptibility to cancer genome aberrations.
Genetic aberrations (lesions) govern the transformation of previously normal cells into cancer cells by changing key signaling pathways within the cells that control cellular proliferation, differentiation and survival. Such lesions are thus considered prime molecular targets for cancer therapy. While some notable examples underscore the clinical relevance of this connection between genetics and drug response, there is a lack of analytical approaches to provide such novel "drug-mutation" combinations in a broad and unbiased fashion. We have therefore collected a panel of genetically and phenotypically characterized nonsmall cell lung cancer (NSCLC) cell lines to systematically screen for drug susceptibility of NSCLC as a function of genetic lesions. We found such genetic lesions to predict activity of geldanamycin-derived Hsp90 inhibitors as well as of the clinically approved SRC/ABL-inhibitor dasatinib. This work may therefore help advancing our understanding of critical oncogenic pathway dependencies and may impact future drug development by defining drug-susceptible patient populations.
Sos
Martin L
ML
Max Planck Institute for Neurological Research with Klaus-Joachim-Zülch Laboratories of the Max Planck Society and the Medical Faculty of the University of Köln, Köln, Germany.
Thomas
Roman K
RK
D016227:Benzoquinones / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D000069439:Dasatinib; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D009154:Mutation / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D013844:Thiazoles / Q000494:pharmacology
D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D000069439:Dasatinib; C001277:geldanamycin