PMID- 22260668
OWN - NLM
STAT- MEDLINE
DCOM- 20120518
LR  - 20220129
IS  - 1470-8752 (Electronic)
IS  - 0300-5127 (Linking)
VI  - 40
IP  - 1
DP  - 2012 Feb
TI  - Tumour cell responses to MEK1/2 inhibitors: acquired resistance and pathway 
      remodelling.
PG  - 73-8
LID - 10.1042/BST20110647 [doi]
AB  - The Raf/MEK1/2 [mitogen-activated protein kinase/ERK 
      (extracellular-signal-regulated kinase) kinase 1/2]/ERK1/2 signalling pathway is 
      frequently activated in human tumours due to mutations in BRAF or KRAS. B-Raf and 
      MEK1/2 inhibitors are currently undergoing clinical evaluation, but their 
      ultimate success is likely to be limited by acquired drug resistance. We have 
      used colorectal cancer cell lines harbouring mutations in B-Raf or K-Ras to model 
      acquired resistance to the MEK1/2 inhibitor selumetinib (AZD6244). 
      Selumetinib-resistant cells were refractory to other MEK1/2 inhibitors in cell 
      proliferation assays and exhibited a marked increase in MEK1/2 and ERK1/2 
      activity and cyclin D1 abundance when assessed in the absence of inhibitor. This 
      was driven by a common mechanism in which resistant cells exhibited an 
      intrachromosomal amplification of their respective driving oncogene, B-Raf V600E 
      or K-RasG13D. Despite the increased signal flux from Raf to MEK1/2, resistant 
      cells maintained in drug actually exhibited the same level of ERK1/2 activity as 
      parental cells, indicating that the pathway is remodelled by feedback controls to 
      reinstate the normal level of ERK1/2 signalling that is required and sufficient 
      to maintain proliferation in these cells. These results provide important new 
      insights into how tumour cells adapt to new therapeutics and highlight the 
      importance of homoeostatic control mechanisms in the Raf/MEK1/2/ERK1/2 signalling 
      cascade.
FAU - Little, Annette S
AU  - Little AS
AD  - Laboratory of Signalling and Cell Fate, The Babraham Institute, Babraham Research 
      Campus, Cambridge CB22 3AT, UK.
FAU - Balmanno, Kathryn
AU  - Balmanno K
FAU - Sale, Matthew J
AU  - Sale MJ
FAU - Smith, Paul D
AU  - Smith PD
FAU - Cook, Simon J
AU  - Cook SJ
LA  - eng
GR  - BBS/E/B/0000C199/BB_/Biotechnology and Biological Sciences Research 
      Council/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 Soc Trans
JT  - Biochemical Society transactions
JID - 7506897
RN  - 0 (AZD 6244)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Benzimidazoles)
RN  - 0 (Drosophila Proteins)
RN  - 0 (KRAS protein, human)
RN  - 0 (Proto-Oncogene Proteins)
RN  - EC 2.7.1.- (msn protein, Drosophila)
RN  - EC 2.7.11.1 (BRAF protein, human)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins B-raf)
RN  - EC 2.7.12.2 (MAP Kinase Kinase 1)
RN  - EC 2.7.12.2 (MAP2K1 protein, human)
RN  - EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
RN  - EC 3.6.5.2 (ras Proteins)
SB  - IM
MH  - Antineoplastic Agents/*pharmacology
MH  - Benzimidazoles/*pharmacology
MH  - Cell Line, Tumor
MH  - Drosophila Proteins
MH  - *Drug Resistance, Neoplasm
MH  - Gene Amplification
MH  - Humans
MH  - MAP Kinase Kinase 1/*antagonists & inhibitors
MH  - MAP Kinase Signaling System/*drug effects
MH  - Neoplasms/drug therapy/genetics/metabolism
MH  - Protein Serine-Threonine Kinases
MH  - Proto-Oncogene Proteins/genetics/metabolism
MH  - Proto-Oncogene Proteins B-raf/genetics/metabolism
MH  - Proto-Oncogene Proteins p21(ras)
MH  - ras Proteins/genetics/metabolism
EDAT- 2012/01/21 06:00
MHDA- 2012/05/19 06:00
CRDT- 2012/01/21 06:00
PHST- 2012/01/21 06:00 [entrez]
PHST- 2012/01/21 06:00 [pubmed]
PHST- 2012/05/19 06:00 [medline]
AID - BST20110647 [pii]
AID - 10.1042/BST20110647 [doi]
PST - ppublish
SO  - Biochem Soc Trans. 2012 Feb;40(1):73-8. doi: 10.1042/BST20110647.