Dney; LA: significant intestine; LI: liver; LU: lung; OE: oesophagus; OV: ovary; PA: pancreas; PL: pleura; SK: skin; SO: soft tissue; ST: stomach; TH: thyroid; UP: upper digestive; UR: urinary (B) The predicted role of PC-Meta identified compensatory mechanisms in MEK inhibition. Red- and green-fills indicates increased and decreased gene expression or activity in drug-resistant cell-lines respectively. Downstream RAF/MEK/ERK and PI3K/AKT/MTOR pathways are indicated in orange boxes and inhibitor is indicated in blue box. (C) Heatmap displaying the expression of genes in the PC-Meta detected compensatory pathways correlated with PD-0325901 resistance in multiple cancer lineages. doi:10.1371/journal.pone.0103050.gPLOS One | plosone.orgCharacterizing Pan-Cancer Mechanisms of Drug SensitivityMeta approach to identify potentially critical compensatory mechanisms by which cancers resist targeted therapies.ConclusionsIn this study, we investigated the inherent determinants of cancer drug response across multiple cancer lineages. For this goal, we created a pan-cancer analysis strategy according to meta-analysis, PC-Meta, and comprehensively characterized known and novel mechanisms of response to both cytotoxic chemotherapies and targeted therapies within the publically offered CCLE resource. Because numerous CCLE compounds weren’t amenable to extensive evaluation resulting from hugely biased pharmacological profiles or lack of reasonable sample sizes, we focused on a subset of 5 drugs that exhibited a broad selection of in vitro sensitivity values across Thyroid Hormone Receptor drug various cancer lineages. Importantly, compared to alternative approaches, our PC-Meta approach consistently demonstrated higher power in identifying potentially relevant markers and capability to infer the mechanisms of response. For TOP1 inhibitors that happen to be dependent on DNA replication and transcription rates, our evaluation predicted cell lines with slower development kinetics as inherently additional drug-resistant irrespective of cancer lineage. While this was not unexpected, our predictions suggested that the cellular growth prices in unique cancer forms could be suppressed through down-regulation of many processes like cell cycle manage, nucleotide synthesis, and RNA translation. The degree of involvement of distinct pathways in each cancer lineage can guide selection of right mixture therapy to circumvent resistance. We further observed that the overexpression of DNA repair genes could be indicative of a genome instability phenotype that could confer intrinsic resistance to TOP1 inhibition. For Panobinostat, a pan-HDAC inhibitor which has been hypothesized to act on cancer cells via a number of diverse mechanisms, we identified the up-regulation of STAT-1/interferon signaling as a principal aspect of inherent resistance across various cancer lineages. The basal overexpression of this pathway has been previously implicated in resistance to both radiotherapy and chemotherapy in lung and breast cancers, where it was suggested to confer resistance to LTB4 Accession genotoxic anxiety and harm as a result of failing to transmit cytotoxic signals. Our benefits expand its significance for more cancer sorts for example those arising from ovarian and oesophageal tissue. Interestingly, our strategy also identified a set of lung-specific markers involved within the caveolarmediated endocytosis signaling, suggesting an essential part of this pathway inside the resistance of lung cancers to Panobinostat. For MEK inhibitors, our PC-Meta analy.
