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Drug Resistance Missense Mutations in Cancer Are Subject to Evolutionary Constraints
Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. (CCBG ; BMC)ORCID iD: 0000-0001-8696-3104
2013 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 12, article id e82059Article in journal (Refereed) Published
Abstract [en]

Several tumor types are sensitive to deactivation of just one or very few genes that are constantly active in the cancer cells,a phenomenon that is termed oncogene addiction'. Drugs that target the products of those oncogenes can yield a temporary relief, and even complete remission. Unfortunately, many patients receiving oncogene-targeted therapies relapse on treatment. This often happens due to somatic mutations in the oncogene (resistance mutations"). 'Compound mutations', which in the context of cancer drug resistance are defined as two or more mutations of the drug target in the same clone may lead to enhanced resistance against the most selective inhibitors. Here, it is shown that the vast majority the resistance mutations occurring in cancer patients treated with tyrosin kinase inhibitors aimed at three different proteins follow an evolutionary pathway. Using bioinforrnatic analysis tools, found that the drug-resistance mutations in the tyrosine kinase domains of Abl1, ALK and exons 20 and 21 of EGFR favour transformations to residues that can be identified in similar positions in evolutionary related proteins. The results demonstrate that evolutionary pressure shapes the mutational landscape in the case of drug-resistance somatic mutations. The constraints on the mutational landscape suggest that it may be possible to counter single drug-resistance point mutations. The observation of relatively many resistance mutations in Abl1, but not in the other genes, is explained by the fact that mutations in Abl1 tend to be biochemically conservative, whereas mutations in EGFR and ALK tend to be radical. Analysis of Abl1 compound mutations suggests that such mutations are more prevalent than hitherto reported and may be more difficult to counter. This supports the notion that such mutations may provide an escape route for targeted cancer drug resistance.

Place, publisher, year, edition, pages
2013. Vol. 8, no 12, article id e82059
National Category
Biochemistry and Molecular Biology
Research subject
Chemistry, Biochemistry
Identifiers
URN: urn:nbn:se:lnu:diva-32099DOI: 10.1371/journal.pone.0082059ISI: 000328745100015Scopus ID: 2-s2.0-84893420223OAI: oai:DiVA.org:lnu-32099DiVA, id: diva2:693980
Available from: 2014-02-05 Created: 2014-02-05 Last updated: 2017-12-06Bibliographically approved

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Friedman, Ran

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