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• W2316080015 startingPage "285" @default.
• W2316080015 abstract "Tumour cells typically exhibit a G1 cell cycle arrest in response to the MEK1/2 [mitogen-activated protein kinase/ERK (extracellular-signal-regulated kinase) kinase 1/2] inhibitor selumetinib, but do not die, and thus they acquire resistance. In the present study we examined the effect of combining selumetinib with the BH3 [BCL2 (B-cell lymphoma 2) homology domain 3]-mimetic BCL2 inhibitor ABT-263. Although either drug alone caused little tumour cell death, the two agents combined to cause substantial caspase-dependent cell death and inhibit long-term clonogenic survival of colorectal cancer and melanoma cell lines with BRAFV600E or RAS mutations. This cell death absolutely required BAX (BCL2-associated X protein) and was inhibited by RNAi (RNA interference)-mediated knockdown of BIM (BCL2-interacting mediator of cell death) in the BRAFV600E-positive COLO205 cell line. When colorectal cancer cell lines were treated with selumetinib plus ABT-263 we observed a striking reduction in the incidence of cells emerging with acquired resistance to selumetinib. Similar results were observed when we combined ABT-263 with the BRAFV600E-selective inhibitor PLX4720, but only in cells expressing BRAFV600E. Finally, cancer cells in which acquired resistance to selumetinib arises through BRAFV600E amplification remained sensitive to ABT-263, whereas selumetinib-resistant HCT116 cells (KRASG13D amplification) were cross-resistant to ABT-263. Thus the combination of a BCL2 inhibitor and an ERK1/2 pathway inhibitor is synthetic lethal in ERK1/2-addicted tumour cells, delays the onset of acquired resistance and in some cases overcomes acquired resistance to selumetinib." @default.
• W2316080015 created "2016-06-24" @default.
• W2316080015 creator A5025815250 @default.
• W2316080015 creator A5080697552 @default.
• W2316080015 date "2013-02-15" @default.
• W2316080015 modified "2023-09-27" @default.
• W2316080015 title "The BH3 mimetic ABT-263 synergizes with the MEK1/2 inhibitor selumetinib/AZD6244 to promote BIM-dependent tumour cell death and inhibit acquired resistance" @default.
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• W2316080015 doi "https://doi.org/10.1042/bj20121212" @default.
• W2316080015 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/23234544" @default.
• W2316080015 hasPublicationYear "2013" @default.
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