Genetic load makes cancer cells more sensitive to common drugs: evidence from Cancer Cell Line Encyclopedia

Abstract Genetic alterations initiate tumors and enable the evolution of drug resistance. The pro-cancer view of mutations is however incomplete, and several studies show that mutational load can reduce tumor fitness. Given its negative effect, genetic load should make tumors more sensitive to antic...

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Autores principales:	Ana B. Pavel, Kirill S. Korolev
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/c67685747c7f4e45815ea603bf2059a7
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spelling	oai:doaj.org-article:c67685747c7f4e45815ea603bf2059a72021-12-02T16:06:05ZGenetic load makes cancer cells more sensitive to common drugs: evidence from Cancer Cell Line Encyclopedia10.1038/s41598-017-02178-12045-2322https://doaj.org/article/c67685747c7f4e45815ea603bf2059a72017-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-02178-1https://doaj.org/toc/2045-2322Abstract Genetic alterations initiate tumors and enable the evolution of drug resistance. The pro-cancer view of mutations is however incomplete, and several studies show that mutational load can reduce tumor fitness. Given its negative effect, genetic load should make tumors more sensitive to anticancer drugs. Here, we test this hypothesis across all major types of cancer from the Cancer Cell Line Encyclopedia, which provides genetic and expression data of 496 cell lines together with their response to 24 common anticancer drugs. We found that the efficacy of 9 out of 24 drugs showed significant association with genetic load in a pan-cancer analysis. The associations for some tissue-drug combinations were remarkably strong, with genetic load explaining up to 83% of the variance in the drug response. Overall, the role of genetic load depended on both the drug and the tissue type with 10 tissues being particularly vulnerable to genetic load. We also identified changes in gene expression associated with increased genetic load, which included cell-cycle checkpoints, DNA damage and apoptosis. Our results show that genetic load is an important component of tumor fitness and can predict drug sensitivity. Beyond being a biomarker, genetic load might be a new, unexplored vulnerability of cancer.Ana B. PavelKirill S. KorolevNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-10 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Ana B. Pavel Kirill S. Korolev Genetic load makes cancer cells more sensitive to common drugs: evidence from Cancer Cell Line Encyclopedia
description	Abstract Genetic alterations initiate tumors and enable the evolution of drug resistance. The pro-cancer view of mutations is however incomplete, and several studies show that mutational load can reduce tumor fitness. Given its negative effect, genetic load should make tumors more sensitive to anticancer drugs. Here, we test this hypothesis across all major types of cancer from the Cancer Cell Line Encyclopedia, which provides genetic and expression data of 496 cell lines together with their response to 24 common anticancer drugs. We found that the efficacy of 9 out of 24 drugs showed significant association with genetic load in a pan-cancer analysis. The associations for some tissue-drug combinations were remarkably strong, with genetic load explaining up to 83% of the variance in the drug response. Overall, the role of genetic load depended on both the drug and the tissue type with 10 tissues being particularly vulnerable to genetic load. We also identified changes in gene expression associated with increased genetic load, which included cell-cycle checkpoints, DNA damage and apoptosis. Our results show that genetic load is an important component of tumor fitness and can predict drug sensitivity. Beyond being a biomarker, genetic load might be a new, unexplored vulnerability of cancer.
format	article
author	Ana B. Pavel Kirill S. Korolev
author_facet	Ana B. Pavel Kirill S. Korolev
author_sort	Ana B. Pavel
title	Genetic load makes cancer cells more sensitive to common drugs: evidence from Cancer Cell Line Encyclopedia
title_short	Genetic load makes cancer cells more sensitive to common drugs: evidence from Cancer Cell Line Encyclopedia
title_full	Genetic load makes cancer cells more sensitive to common drugs: evidence from Cancer Cell Line Encyclopedia
title_fullStr	Genetic load makes cancer cells more sensitive to common drugs: evidence from Cancer Cell Line Encyclopedia
title_full_unstemmed	Genetic load makes cancer cells more sensitive to common drugs: evidence from Cancer Cell Line Encyclopedia
title_sort	genetic load makes cancer cells more sensitive to common drugs: evidence from cancer cell line encyclopedia
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/c67685747c7f4e45815ea603bf2059a7
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Genetic load makes cancer cells more sensitive to common drugs: evidence from Cancer Cell Line Encyclopedia

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