Combining Mutational Signatures, Clonal Fitness, and Drug Affinity to Define Drug-Specific Resistance Mutations in Cancer.
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Embargo End Date
ICR Authors
Authors
Kaserer, T
Blagg, J
Blagg, J
Document Type
Journal Article
Date
2018-11-15
Date Accepted
2018-07-26
Abstract
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.
Citation
Cell chemical biology, 2018, 25 (11), pp. 1359 - 1371.e2
Source Title
Publisher
CELL PRESS
ISSN
2451-9456
eISSN
2451-9448
Collections
Research Team
In Silico Medicinal Chemistry
Medicinal Chemistry 1
Medicinal Chemistry 1