title: A meta-analysis approach for characterizing pan-cancer mechanisms of drug sensitivity in cell lines.
abstract: Understanding the heterogeneous drug response of cancer patients is essential to precision oncology. Pioneering genomic analyses of individual cancer subtypes have begun to identify key determinants of resistance, including up-regulation of multi-drug resistance (MDR) genes and mutational alterations of drug targets. However, these alterations are sufficient to explain only a minority of the population, and additional mechanisms of drug resistance or sensitivity are required to explain the remaining spectrum of patient responses to ultimately achieve the goal of precision oncology. We hypothesized that a pan-cancer analysis of in vitro drug sensitivities across numerous cancer lineages will improve the detection of statistical associations and yield more robust and, importantly, recurrent determinants of response. In this study, we developed a statistical framework based on the meta-analysis of expression profiles to identify pan-cancer markers and mechanisms of drug response. Using the Cancer Cell Line Encyclopaedia (CCLE), a large panel of several hundred cancer cell lines from numerous distinct lineages, we characterized both known and novel mechanisms of response to cytotoxic drugs including inhibitors of Topoisomerase 1 (TOP1; Topotecan, Irinotecan) and targeted therapies including inhibitors of histone deacetylases (HDAC; Panobinostat) and MAP/ERK kinases (MEK; PD-0325901, AZD6244). Notably, our analysis implicated reduced replication and transcriptional rates, as well as deficiency in DNA damage repair genes in resistance to TOP1 inhibitors. The constitutive activation of several signaling pathways including the interferon/STAT-1 pathway was implicated in resistance to the pan-HDAC inhibitor. Finally, a number of dysregulations upstream of MEK were identified as compensatory mechanisms of resistance to the MEK inhibitors. In comparison to alternative pan-cancer analysis strategies, our approach can better elucidate relevant drug response mechanisms. Moreover, the compendium of putative markers and mechanisms identified through our analysis can serve as a foundation for future studies into these drugs.
authors.affiliation: Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, Canada.
authors.forename: Kendric
authors.initials: K
authors.lastname: Wang
authors.affiliation: Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, Canada; CIHR/MSHFR Bioinformatics Training Program, University of British Columbia, Vancouver, Canada.
authors.forename: Raunak
authors.initials: R
authors.lastname: Shrestha
authors.affiliation: Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, Canada.
authors.forename: Alexander W
authors.initials: AW
authors.lastname: Wyatt
authors.affiliation: Novartis Pharmaceuticals, Oncology Division, Basal, Switzerland.
authors.forename: Anupama
authors.initials: A
authors.lastname: Reddy
authors.affiliation: Novartis Pharmaceuticals, Oncology Division, Basal, Switzerland.
authors.forename: Joseph
authors.initials: J
authors.lastname: Lehár
authors.affiliation: Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, Canada; Department of Urologic Sciences, the University of British Columbia, Vancouver, Canada.
authors.forename: Yuzhou
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, Canada.
authors.forename: Anna
authors.initials: A
authors.lastname: Lapuk
authors.affiliation: Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, Canada; Department of Urologic Sciences, the University of British Columbia, Vancouver, Canada.
authors.forename: Colin C
authors.initials: CC
authors.lastname: Collins
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000235:genetics; D045744:Cell Line, Tumor; D004260:DNA Repair / Q000187:drug effects / Q000235:genetics; D018432:Drug Resistance, Multiple / Q000187:drug effects / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D007372:Interferons / Q000235:genetics; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D050794:STAT1 Transcription Factor / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D059004:Topoisomerase I Inhibitors / Q000494:pharmacology; D059467:Transcriptome / Q000187:drug effects / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D056572:Histone Deacetylase Inhibitors; D050794:STAT1 Transcription Factor; D059004:Topoisomerase I Inhibitors; D007372:Interferons; D020929:Mitogen-Activated Protein Kinase Kinases