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Cell Chem Biol. 2018 Nov 15;25(11):1359-1371.e2. doi: 10.1016/j.chembiol.2018.07.013. Epub 2018 Aug 23.

Combining Mutational Signatures, Clonal Fitness, and Drug Affinity to Define Drug-Specific Resistance Mutations in Cancer.

Author information

1
Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, UK. Electronic address: teresa.kaserer@icr.ac.uk.
2
Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, UK. Electronic address: julian.blagg@icr.ac.uk.

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.

KEYWORDS:

clonal fitness; drug resistance; mutation signature; resistance hotspot; targeted cancer drugs

PMID:
30146241
PMCID:
PMC6242700
DOI:
10.1016/j.chembiol.2018.07.013
[Indexed for MEDLINE]
Free PMC Article

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