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MEK-independent survival of B-RAFV600E melanoma cells selected for resistance to apoptosis induced by the RAF inhibitor PLX4720.
- Source :
-
Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2011 Feb 15; Vol. 17 (4), pp. 721-30. Date of Electronic Publication: 2010 Nov 18. - Publication Year :
- 2011
-
Abstract
- Purpose: To examine mechanisms that determine long-term responses of B-RAF(V600E) melanoma cells to B-RAF inhibitors.<br />Experimental Design: B-RAF(V600E) melanoma cells were exposed to the B-RAF inhibitor PLX4720 for prolonged periods to select for cells resistant to apoptosis induced by the inhibitor. The resultant cells were analyzed for activation of extracellular signal regulated kinase (ERK), MAP/ERK kinase (MEK), and Akt, and related signals. Their roles in survival of the cells were also examined.<br />Results: B-RAF(V600E) melanoma cells selected for resistant to PLX4720-induced apoptosis retained the V600E mutation in B-RAF, and proliferated steadily in the presence of the inhibitor, albeit with slow growth rate. These cells displayed high levels of ERK activation, that is, at least in part, independent of the conventional RAF/MEK/ERK pathway, as MEK activation was low and inhibition of MEK did not significantly block activation of ERK. In contrast, extracellular signals appeared involved. This was associated with elevated activation of the phosphoinositide 3-kinase (PI3k)/Akt pathway and could be inhibited by serum starvation and inhibition of PI3k/Akt. Inhibition of MEK did not impact on survival of these cells, whereas serum starvation, inhibition of PI3K/Akt, and inhibition of ERK1/2 reduced their viability.<br />Conclusions: These results indicate that sensitivity to induction of apoptosis may be a major determinant of long-term responses of B-RAF(V600E) melanomas to specific inhibitors and suggest that rebound melanoma growth after initial treatment with the inhibitors may not be responsive to MEK inhibitors, but may be susceptible to inhibition of the PI3k/Akt pathway.<br /> (©2010 AACR.)
- Subjects :
- Butadienes pharmacology
Cell Line, Tumor
Cell Survival drug effects
Cell Survival genetics
Chromones pharmacology
Culture Media
Enzyme Activation
Enzyme Inhibitors pharmacology
Extracellular Signal-Regulated MAP Kinases metabolism
Gene Expression Regulation, Neoplastic
Humans
MAP Kinase Kinase 1 antagonists & inhibitors
Morpholines pharmacology
Nitriles pharmacology
Phosphatidylinositol 3-Kinases metabolism
Phosphoinositide-3 Kinase Inhibitors
Proto-Oncogene Proteins c-akt metabolism
Signal Transduction
Antineoplastic Agents pharmacology
Apoptosis genetics
Drug Resistance, Neoplasm
Indoles pharmacology
MAP Kinase Kinase 1 metabolism
Proto-Oncogene Proteins B-raf antagonists & inhibitors
Sulfonamides pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1557-3265
- Volume :
- 17
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Clinical cancer research : an official journal of the American Association for Cancer Research
- Publication Type :
- Academic Journal
- Accession number :
- 21088259
- Full Text :
- https://doi.org/10.1158/1078-0432.CCR-10-2225