PMID- 23234544
OWN - NLM
STAT- MEDLINE
DCOM- 20130411
LR  - 20240210
IS  - 1470-8728 (Electronic)
IS  - 0264-6021 (Linking)
VI  - 450
IP  - 2
DP  - 2013 Mar 1
TI  - The BH3 mimetic ABT-263 synergizes with the MEK1/2 inhibitor selumetinib/AZD6244 
      to promote BIM-dependent tumour cell death and inhibit acquired resistance.
PG  - 285-94
LID - 10.1042/BJ20121212 [doi]
AB  - 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.
FAU - Sale, Matthew J
AU  - Sale MJ
AD  - Signalling Laboratory, The Babraham Institute, Babraham Research Campus, 
      Cambridge CB22 3AT, UK. matthew.sale@babraham.ac.uk
FAU - Cook, Simon J
AU  - Cook SJ
LA  - eng
GR  - C488/A14867/CRUK_/Cancer Research UK/United Kingdom
GR  - BBS/E/B/0000H151/BB_/Biotechnology and Biological Sciences Research 
      Council/United Kingdom
GR  - BB/F0158521/1/BB_/Biotechnology and Biological Sciences Research Council/United 
      Kingdom
GR  - BB/E02162X/1/BB_/Biotechnology and Biological Sciences Research Council/United 
      Kingdom
GR  - 14867/CRUK_/Cancer Research UK/United Kingdom
GR  - BBS/E/B/000C0419/BB_/Biotechnology and Biological Sciences Research 
      Council/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Biochem J
JT  - The Biochemical journal
JID - 2984726R
RN  - 0 (AZD 6244)
RN  - 0 (Aniline Compounds)
RN  - 0 (Benzimidazoles)
RN  - 0 (Sulfonamides)
RN  - 0 (bcl-2-Associated X Protein)
RN  - EC 2.7.1.- (MAP2K2 protein, human)
RN  - EC 2.7.12.2 (MAP Kinase Kinase 1)
RN  - EC 2.7.12.2 (MAP Kinase Kinase 2)
RN  - EC 2.7.12.2 (MAP2K1 protein, human)
RN  - XKJ5VVK2WD (navitoclax)
SB  - IM
MH  - Aniline Compounds/*pharmacology
MH  - Apoptosis
MH  - Benzimidazoles/*pharmacology
MH  - *Cell Death
MH  - Cell Line, Tumor
MH  - Drug Resistance, Neoplasm
MH  - HT29 Cells
MH  - Humans
MH  - MAP Kinase Kinase 1/*antagonists & inhibitors/metabolism
MH  - MAP Kinase Kinase 2/*antagonists & inhibitors/metabolism
MH  - MAP Kinase Signaling System
MH  - RNA Interference
MH  - Sulfonamides/*pharmacology
MH  - bcl-2-Associated X Protein/metabolism
EDAT- 2012/12/14 06:00
MHDA- 2013/04/12 06:00
CRDT- 2012/12/14 06:00
PHST- 2012/12/14 06:00 [entrez]
PHST- 2012/12/14 06:00 [pubmed]
PHST- 2013/04/12 06:00 [medline]
AID - BJ20121212 [pii]
AID - 10.1042/BJ20121212 [doi]
PST - ppublish
SO  - Biochem J. 2013 Mar 1;450(2):285-94. doi: 10.1042/BJ20121212.