PMID- 25109949
OWN - NLM
STAT- MEDLINE
DCOM- 20150511
LR  - 20240210
IS  - 1470-8752 (Electronic)
IS  - 0300-5127 (Linking)
VI  - 42
IP  - 4
DP  - 2014 Aug
TI  - MAPK pathway inhibition in melanoma: resistance three ways.
PG  - 727-32
LID - 10.1042/BST20140020 [doi]
AB  - The serine threonine kinases BRAF and MEK [MAPK (mitogen-activated protein 
      kinase)/ERK (extracellular-signal-regulated kinase) kinase] are major regulators 
      of the ERK/MAPK pathway, which is deregulated in the majority of melanomas. 
      Targeting BRAF is an effective therapy for advanced melanoma, but patients 
      progress due to the development of resistance. This 'acquired resistance' is 
      thought to be based on a minority of tumour cell populations that are resistant 
      and will eventually re-establish tumour growth even in the presence of drug. In 
      particular, mutations, amplifications or overexpression of genes encoding 
      regulators of the MAPK pathway can confer this resistance, because it allows the 
      melanoma cells to bypass inhibitor action by stimulating ERK activation through 
      alternative routes. Furthermore, there are mechanisms that produce resistance by 
      enhancing the tolerance of melanoma cells to the cytotoxic effects of the drug. 
      These compensatory mechanisms can activate survival signals in the melanoma cells 
      without reactivating ERK. Besides these cell-autonomous resistance mechanisms, 
      stromal fibroblasts in the tumour microenvironment have been identified as a 
      potential source of resistance, because these cells can produce growth factors 
      that reactivate ERK through paracrine signalling. Understanding and further 
      identifying mechanisms of resistance is crucial for the future treatment of 
      advanced melanoma, because this can inform the design of improved therapies with 
      more durable responses.
FAU - Wellbrock, Claudia
AU  - Wellbrock C
AD  - *Manchester Cancer Research Centre, Wellcome Trust Center for Cell Matrix 
      Research, Faculty of Life Sciences, University of Manchester, Michael Smith 
      Building, Oxford Road, Manchester M13 9PT, U.K.
LA  - eng
GR  - 16416/CRUK_/Cancer Research UK/United Kingdom
GR  - C11591/A16416/CRUK_/Cancer Research UK/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Review
PL  - England
TA  - Biochem Soc Trans
JT  - Biochemical Society transactions
JID - 7506897
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Microphthalmia-Associated Transcription Factor)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins B-raf)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/therapeutic use
MH  - Drug Resistance, Neoplasm/genetics/physiology
MH  - Humans
MH  - Melanoma/drug therapy/genetics/*metabolism
MH  - Microphthalmia-Associated Transcription Factor/genetics/metabolism
MH  - Mitogen-Activated Protein Kinases/genetics/*metabolism
MH  - Proto-Oncogene Proteins B-raf/genetics/metabolism
MH  - Signal Transduction/drug effects
EDAT- 2014/08/12 06:00
MHDA- 2015/05/12 06:00
CRDT- 2014/08/12 06:00
PHST- 2014/08/12 06:00 [entrez]
PHST- 2014/08/12 06:00 [pubmed]
PHST- 2015/05/12 06:00 [medline]
AID - BST20140020 [pii]
AID - 10.1042/BST20140020 [doi]
PST - ppublish
SO  - Biochem Soc Trans. 2014 Aug;42(4):727-32. doi: 10.1042/BST20140020.