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Biotech / Medical : Indications -- Cancer
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From: scaram(o)uche12/14/2012 6:07:26 PM
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Biochem J. 2012 Dec 13. [Epub ahead of print]

The BH3-mimetic ABT-263 synergises with the MEK1/2 inhibitor selumetinib/AZD6244 to promote BIM-dependent tumour cell death and inhibit acquired resistance.

Sale MJ, Cook SJ.

Tumour cells typically exhibit a G1 cell cycle arrest in response to the MEK1/2 inhibitor selumetinib but do not die and so acquire resistance. Here we examined the effect of combining selumetinib with the BH3-mimetic, BCL2 inhibitor ABT-263. Whilst 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 and was inhibited by RNAi-mediated knockdown of BIM in the BRAFV600E-positive COLO205 cell line. When colorectal cancer cell lines were treated with selumetinib+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.

(Wo!)
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