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A network approach to understanding drug resistance (235.2)
Author(s) -
Pe'er Dana
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.235.2
Subject(s) - mapk/erk pathway , phenotype , epigenetics , biology , computational biology , context (archaeology) , phenotypic screening , genetics , signal transduction , gene , paleontology
New drugs that target MAPK‐activated melanomas show good clinical results, but with varied outcomes, both in vitro and in patients. The reasons for the phenotypic heterogeneity are still unknown. Here we aim at explaining the phenotypic variability by integrating data of different types to infer network state and rewiring. We focus at the heterogeneous response of melanoma to MAPK pathway inhibition. First, we use pre‐ and post‐MAPK inhibition transcription data to identify downstream targets and pathways that interact with the MAPK pathway. We show that the network is vastly rewired in different melanoma cell lines. For example, we show that most downstream targets of the MAPK pathway are context‐specific ‐ under the control of the pathway in a subset of cell lines. We then use other data types, such as DNA copy number, epigenetics and mutations to explain the network rewiring and to link genotype to phenotype. Using our approach, we identify new vulnerabilities that can be targeted to enhance the phenotypic response to MAPK inhibition. We experimental confirm several treatment combinations and show that the cytotoxic response to MAPK inhibition can be enhanced by different drugs in different cell lines. Our analysis demonstrates the value of system‐wide perturbation data in predicting drug response in the era of personalized medicine.