Targeting the DNA replication stress phenotype of KRAS mutant cancer cells

Abstract Mutant KRAS is a common tumor driver and frequently confers resistance to anti-cancer treatments such as radiation. DNA replication stress in these tumors may constitute a therapeutic liability but is poorly understood. Here, using single-molecule DNA fiber analysis, we first characterized...

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Autores principales:	Tara Al Zubaidi, O. H. Fiete Gehrisch, Marie-Michelle Genois, Qi Liu, Shan Lu, Jong Kung, Yunhe Xie, Jan Schuemann, Hsiao-Ming Lu, Aaron N. Hata, Lee Zou, Kerstin Borgmann, Henning Willers
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/c9f65698ab184d44a3f15db972aba8ea
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spelling	oai:doaj.org-article:c9f65698ab184d44a3f15db972aba8ea2021-12-02T14:11:32ZTargeting the DNA replication stress phenotype of KRAS mutant cancer cells10.1038/s41598-021-83142-y2045-2322https://doaj.org/article/c9f65698ab184d44a3f15db972aba8ea2021-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-83142-yhttps://doaj.org/toc/2045-2322Abstract Mutant KRAS is a common tumor driver and frequently confers resistance to anti-cancer treatments such as radiation. DNA replication stress in these tumors may constitute a therapeutic liability but is poorly understood. Here, using single-molecule DNA fiber analysis, we first characterized baseline replication stress in a panel of unperturbed isogenic and non-isogenic cancer cell lines. Correlating with the observed enhanced replication stress we found increased levels of cytosolic double-stranded DNA in KRAS mutant compared to wild-type cells. Yet, despite this phenotype replication stress-inducing agents failed to selectively impact KRAS mutant cells, which were protected by CHK1. Similarly, most exogenous stressors studied did not differentially augment cytosolic DNA accumulation in KRAS mutant compared to wild-type cells. However, we found that proton radiation was able to slow fork progression and preferentially induce fork stalling in KRAS mutant cells. Proton treatment also partly reversed the radioresistance associated with mutant KRAS. The cellular effects of protons in the presence of KRAS mutation clearly contrasted that of other drugs affecting replication, highlighting the unique nature of the underlying DNA damage caused by protons. Taken together, our findings provide insight into the replication stress response associated with mutated KRAS, which may ultimately yield novel therapeutic opportunities.Tara Al ZubaidiO. H. Fiete GehrischMarie-Michelle GenoisQi LiuShan LuJong KungYunhe XieJan SchuemannHsiao-Ming LuAaron N. HataLee ZouKerstin BorgmannHenning WillersNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Tara Al Zubaidi O. H. Fiete Gehrisch Marie-Michelle Genois Qi Liu Shan Lu Jong Kung Yunhe Xie Jan Schuemann Hsiao-Ming Lu Aaron N. Hata Lee Zou Kerstin Borgmann Henning Willers Targeting the DNA replication stress phenotype of KRAS mutant cancer cells
description	Abstract Mutant KRAS is a common tumor driver and frequently confers resistance to anti-cancer treatments such as radiation. DNA replication stress in these tumors may constitute a therapeutic liability but is poorly understood. Here, using single-molecule DNA fiber analysis, we first characterized baseline replication stress in a panel of unperturbed isogenic and non-isogenic cancer cell lines. Correlating with the observed enhanced replication stress we found increased levels of cytosolic double-stranded DNA in KRAS mutant compared to wild-type cells. Yet, despite this phenotype replication stress-inducing agents failed to selectively impact KRAS mutant cells, which were protected by CHK1. Similarly, most exogenous stressors studied did not differentially augment cytosolic DNA accumulation in KRAS mutant compared to wild-type cells. However, we found that proton radiation was able to slow fork progression and preferentially induce fork stalling in KRAS mutant cells. Proton treatment also partly reversed the radioresistance associated with mutant KRAS. The cellular effects of protons in the presence of KRAS mutation clearly contrasted that of other drugs affecting replication, highlighting the unique nature of the underlying DNA damage caused by protons. Taken together, our findings provide insight into the replication stress response associated with mutated KRAS, which may ultimately yield novel therapeutic opportunities.
format	article
author	Tara Al Zubaidi O. H. Fiete Gehrisch Marie-Michelle Genois Qi Liu Shan Lu Jong Kung Yunhe Xie Jan Schuemann Hsiao-Ming Lu Aaron N. Hata Lee Zou Kerstin Borgmann Henning Willers
author_facet	Tara Al Zubaidi O. H. Fiete Gehrisch Marie-Michelle Genois Qi Liu Shan Lu Jong Kung Yunhe Xie Jan Schuemann Hsiao-Ming Lu Aaron N. Hata Lee Zou Kerstin Borgmann Henning Willers
author_sort	Tara Al Zubaidi
title	Targeting the DNA replication stress phenotype of KRAS mutant cancer cells
title_short	Targeting the DNA replication stress phenotype of KRAS mutant cancer cells
title_full	Targeting the DNA replication stress phenotype of KRAS mutant cancer cells
title_fullStr	Targeting the DNA replication stress phenotype of KRAS mutant cancer cells
title_full_unstemmed	Targeting the DNA replication stress phenotype of KRAS mutant cancer cells
title_sort	targeting the dna replication stress phenotype of kras mutant cancer cells
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/c9f65698ab184d44a3f15db972aba8ea
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Targeting the DNA replication stress phenotype of KRAS mutant cancer cells

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