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Combining Mutational Signatures, Clonal Fitness, and Drug Affinity to Define Drug-Specific Resistance Mutations in Cancer
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 m...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cell Press
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6242700/ https://www.ncbi.nlm.nih.gov/pubmed/30146241 http://dx.doi.org/10.1016/j.chembiol.2018.07.013 |
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author | Kaserer, Teresa Blagg, Julian |
author_facet | Kaserer, Teresa Blagg, Julian |
author_sort | Kaserer, Teresa |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6242700 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Cell Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-62427002018-11-21 Combining Mutational Signatures, Clonal Fitness, and Drug Affinity to Define Drug-Specific Resistance Mutations in Cancer Kaserer, Teresa Blagg, Julian Cell Chem Biol Article 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. Cell Press 2018-11-15 /pmc/articles/PMC6242700/ /pubmed/30146241 http://dx.doi.org/10.1016/j.chembiol.2018.07.013 Text en © 2018 The Author(s) http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Kaserer, Teresa Blagg, Julian Combining Mutational Signatures, Clonal Fitness, and Drug Affinity to Define Drug-Specific Resistance Mutations in Cancer |
title | Combining Mutational Signatures, Clonal Fitness, and Drug Affinity to Define Drug-Specific Resistance Mutations in Cancer |
title_full | Combining Mutational Signatures, Clonal Fitness, and Drug Affinity to Define Drug-Specific Resistance Mutations in Cancer |
title_fullStr | Combining Mutational Signatures, Clonal Fitness, and Drug Affinity to Define Drug-Specific Resistance Mutations in Cancer |
title_full_unstemmed | Combining Mutational Signatures, Clonal Fitness, and Drug Affinity to Define Drug-Specific Resistance Mutations in Cancer |
title_short | Combining Mutational Signatures, Clonal Fitness, and Drug Affinity to Define Drug-Specific Resistance Mutations in Cancer |
title_sort | combining mutational signatures, clonal fitness, and drug affinity to define drug-specific resistance mutations in cancer |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6242700/ https://www.ncbi.nlm.nih.gov/pubmed/30146241 http://dx.doi.org/10.1016/j.chembiol.2018.07.013 |
work_keys_str_mv | AT kasererteresa combiningmutationalsignaturesclonalfitnessanddrugaffinitytodefinedrugspecificresistancemutationsincancer AT blaggjulian combiningmutationalsignaturesclonalfitnessanddrugaffinitytodefinedrugspecificresistancemutationsincancer |