Drug resistance missense mutations in cancer are subject to evolutionary constraints.

Several tumour 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. Un...

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Autor principal:	Ran Friedman
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/93a48e6a78cf47b1820bcbc58988b719
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spelling	oai:doaj.org-article:93a48e6a78cf47b1820bcbc58988b7192021-11-18T08:41:03ZDrug resistance missense mutations in cancer are subject to evolutionary constraints.1932-620310.1371/journal.pone.0082059https://doaj.org/article/93a48e6a78cf47b1820bcbc58988b7192013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24376513/?tool=EBIhttps://doaj.org/toc/1932-6203Several tumour 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 of the resistance mutations occurring in cancer patients treated with tyrosin kinase inhibitors aimed at three different proteins follow an evolutionary pathway. Using bioinformatic analysis tools, it is 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.Ran FriedmanPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 12, p e82059 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Ran Friedman Drug resistance missense mutations in cancer are subject to evolutionary constraints.
description	Several tumour 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 of the resistance mutations occurring in cancer patients treated with tyrosin kinase inhibitors aimed at three different proteins follow an evolutionary pathway. Using bioinformatic analysis tools, it is 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.
format	article
author	Ran Friedman
author_facet	Ran Friedman
author_sort	Ran Friedman
title	Drug resistance missense mutations in cancer are subject to evolutionary constraints.
title_short	Drug resistance missense mutations in cancer are subject to evolutionary constraints.
title_full	Drug resistance missense mutations in cancer are subject to evolutionary constraints.
title_fullStr	Drug resistance missense mutations in cancer are subject to evolutionary constraints.
title_full_unstemmed	Drug resistance missense mutations in cancer are subject to evolutionary constraints.
title_sort	drug resistance missense mutations in cancer are subject to evolutionary constraints.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/93a48e6a78cf47b1820bcbc58988b719
work_keys_str_mv	AT ranfriedman drugresistancemissensemutationsincanceraresubjecttoevolutionaryconstraints
_version_	1718421459272990720

Drug resistance missense mutations in cancer are subject to evolutionary constraints.

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