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• W3136109663 abstract "Mutations and gene amplifications that confer drug resistance emerge frequently during chemotherapy, but their mechanism and timing is poorly understood. Here, we investigate BRAFV600E amplification events that underlie resistance to the MEK inhibitor selumetinib (AZD6244/ARRY-142886) in COLO205 cells, a well-characterised model for reproducible emergence of drug resistance, and show that de novo amplification of BRAF is the primary path to resistance irrespective of pre-existing amplifications. Selumetinib causes long-term G1 arrest accompanied by reduced expression of DNA replication and repair genes, but cells stochastically re-enter the cell cycle during treatment despite continued repression of pERK1/2. Most DNA replication and repair genes are re-expressed as cells enter S and G2, however, mRNAs encoding a subset of factors important for error-free replication and chromosome segregation including TIPIN, PLK2 and PLK3 remain at low abundance. This suggests that DNA replication in drug is more error prone and provides an explanation for the DNA damage observed under long-term RAF-MEK-ERK1/2 pathway inhibition. To test the hypothesis that DNA replication in drug promotes de novo BRAF amplification, we exploited the combination of palbociclib and selumetinib. Combined treatment with selumetinib and a dose of palbociclib sufficient to reinforce G1 arrest in selumetinib-sensitive cells, but not to impair proliferation of resistant cells, delays the emergence of resistant colonies, meaning that escape from G1 arrest is critical in the formation of resistant clones. Our findings demonstrate that acquisition of MEK inhibitor resistance often occurs through de novo gene amplification and can be suppressed by impeding cell cycle entry in drug." @default.
• W3136109663 created "2021-03-29" @default.
• W3136109663 creator A5023627324 @default.
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• W3136109663 creator A5048068853 @default.
• W3136109663 creator A5090740939 @default.
• W3136109663 date "2021-03-23" @default.
• W3136109663 modified "2023-10-18" @default.
• W3136109663 title "DNA replication during acute MEK inhibition drives acquisition of resistance through amplification of the BRAF oncogene" @default.
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• W3136109663 doi "https://doi.org/10.1101/2021.03.23.436572" @default.
• W3136109663 hasPublicationYear "2021" @default.
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• W3136109663 hasAuthorship W3136109663A5048068853 @default.

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