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

Abstract

Tumour cells typically exhibit a G(1) 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 BRAF(V600E) 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 BRAF(V600E)-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 BRAF(V600E)-selective inhibitor PLX4720, but only in cells expressing BRAF(V600E). Finally, cancer cells in which acquired resistance to selumetinib arises through BRAF(V600E) amplification remained sensitive to ABT-263, whereas selumetinib-resistant HCT116 cells (KRAS(G13D) 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.

• Authors: Matthew J Sale, Simon J Cook
• Journal: The Biochemical journal (Biochem J) Vol. 450 Issue 2 Pg. 285-94 (Mar 01 2013) ISSN: 1470-8728 [Electronic] England
• PMID: 23234544 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• AZD 6244
• Aniline Compounds
• Benzimidazoles
• Sulfonamides
• bcl-2-Associated X Protein
• MAP2K2 protein, human
• MAP Kinase Kinase 1
• MAP Kinase Kinase 2
• MAP2K1 protein, human
• navitoclax

Topics

• Aniline Compounds (pharmacology)
• Apoptosis
• Benzimidazoles (pharmacology)
• Cell Death
• Cell Line, Tumor
• Drug Resistance, Neoplasm
• HT29 Cells
• Humans
• MAP Kinase Kinase 1 (antagonists & inhibitors, metabolism)
• MAP Kinase Kinase 2 (antagonists & inhibitors, metabolism)
• MAP Kinase Signaling System
• RNA Interference
• Sulfonamides (pharmacology)
• bcl-2-Associated X Protein (metabolism)