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• W4378515903 endingPage "8717" @default.
• W4378515903 startingPage "8717" @default.
• W4378515903 abstract "Resistance to chemotherapy is a leading cause of treatment failure. Drug resistance mechanisms involve mutations in specific proteins or changes in their expression levels. It is commonly understood that resistance mutations happen randomly prior to treatment and are selected during the treatment. However, the selection of drug-resistant mutants in culture could be achieved by multiple drug exposures of cloned genetically identical cells and thus cannot result from the selection of pre-existent mutations. Accordingly, adaptation must involve the generation of mutations de novo upon drug treatment. Here we explored the origin of resistance mutations to a widely used Top1 inhibitor, irinotecan, which triggers DNA breaks, causing cytotoxicity. The resistance mechanism involved the gradual accumulation of recurrent mutations in non-coding regions of DNA at Top1-cleavage sites. Surprisingly, cancer cells had a higher number of such sites than the reference genome, which may define their increased sensitivity to irinotecan. Homologous recombination repairs of DNA double-strand breaks at these sites following initial drug exposures gradually reverted cleavage-sensitive cancer sequences back to cleavage-resistant normal sequences. These mutations reduced the generation of DNA breaks upon subsequent exposures, thus gradually increasing drug resistance. Together, large target sizes for mutations and their Top1-guided generation lead to their gradual and rapid accumulation, synergistically accelerating the development of resistance." @default.
• W4378515903 created "2023-05-28" @default.
• W4378515903 creator A5012954582 @default.
• W4378515903 creator A5014206172 @default.
• W4378515903 creator A5022625213 @default.
• W4378515903 creator A5023222656 @default.
• W4378515903 creator A5025814998 @default.
• W4378515903 creator A5027850583 @default.
• W4378515903 creator A5029466944 @default.
• W4378515903 creator A5074099022 @default.
• W4378515903 creator A5084135451 @default.
• W4378515903 date "2023-05-13" @default.
• W4378515903 modified "2023-10-17" @default.
• W4378515903 title "Evolution of Resistance to Irinotecan in Cancer Cells Involves Generation of Topoisomerase-Guided Mutations in Non-Coding Genome That Reduce the Chances of DNA Breaks" @default.
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