Combining Mutational Signatures, Clonal Fitness, and Drug Affinity to Define Drug-Specific Resistance Mutations in Cancer.
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Date
2018-11-15ICR Author
Author
Kaserer, T
Blagg, J
Type
Journal Article
Metadata
Show full item recordAbstract
The emergence of mutations that confer resistance to molecularly targeted therapeutics is dependent upon the effect of each mutation on drug affinity for the target protein, the clonal fitness of cells harboring the mutation, and the probability that each variant can be generated by DNA codon base mutation. We present a computational workflow that combines these three factors to identify mutations likely to arise upon drug treatment in a particular tumor type. The Osprey-based workflow is validated using a comprehensive dataset of ERK2 mutations and is applied to small-molecule drugs and/or therapeutic antibodies targeting KIT, EGFR, Abl, and ALK. We identify major clinically observed drug-resistant mutations for drug-target pairs and highlight the potential to prospectively identify probable drug resistance mutations.
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https://www.sciencedirect.com/science/article/pii/S2451945618302654?via=ihubCollections
Subject
Humans
Neoplasms
Mitogen-Activated Protein Kinase 1
Antineoplastic Agents
DNA Mutational Analysis
Drug Resistance, Neoplasm
Mutation
Models, Molecular
Software
Small Molecule Libraries
Workflow
Molecular Targeted Therapy
Research team
In Silico Medicinal Chemistry
Medicinal Chemistry 1
Language
eng
Date accepted
2018-07-26
License start date
2018-11
Citation
Cell chemical biology, 2018, 25 (11), pp. 1359 - 1371.e2
Publisher
CELL PRESS