Back to Search
Start Over
Combined targeting of MEK/MAPK and PI3K/Akt signalling in multiple myeloma
- Source :
- British Journal of Haematology. 159:430-440
- Publication Year :
- 2012
- Publisher :
- Wiley, 2012.
-
Abstract
- Summary So-called RAS-dependent pathways, such as those signalling via mitogen-activated protein kinase kinase (MEK)/mitogen-activated protein kinase (MAPK) and phosphoinositide-3 kinase (PI3K)/Akt, are implicated in proliferation and survival of multiple myeloma (MM) cells. However, the effects of their combined blockade and its potential therapeutic utility for the treatment of RAS-mutated MM have not systematically been analysed. Here, we tested the functional consequences of single versus combined inhibition of the MEK/MAPK and PI3K/Akt pathways in a large series of primary MM samples (n = 55) and MM cell lines (n = 11). Additionally, the anti-myeloma activity of different treatments was analysed with respect to the RAS mutation status. PI3K/Akt blockade was generally more pro-apoptotic than blockade of MEK/MAPK both in cell lines and in primary MM samples. Simultaneous blockade of both pathways led to significantly enhanced anti-myeloma activity in 75% of primary MM samples, whereas the remainder was largely resistant. Resistance to combination blockade was exclusively observed in RAS wildtype cases, whereas sensitivity was noted in RAS wildtype and in RAS mutated MM. These results suggest that oncogenic RAS is a predictor of sensitivity to combination treatment with PI3K/Akt and MEK/MAPK inhibitors and that such an approach might therefore be beneficial for this genetically well-defined subgroup of MM patients.
- Subjects :
- MAPK/ERK pathway
MAP Kinase Signaling System
Kinase
Chemistry
Apoptosis
Hematology
Cell biology
Blockade
Phosphatidylinositol 3-Kinases
Genes, ras
Cell culture
Cell Line, Tumor
Anti-apoptotic Ras signalling cascade
Mutation
ras Proteins
Cancer research
Humans
Enzyme Inhibitors
Mitogen-Activated Protein Kinases
Multiple Myeloma
Protein kinase A
Proto-Oncogene Proteins c-akt
Protein kinase B
PI3K/AKT/mTOR pathway
Phosphoinositide-3 Kinase Inhibitors
Subjects
Details
- ISSN :
- 00071048
- Volume :
- 159
- Database :
- OpenAIRE
- Journal :
- British Journal of Haematology
- Accession number :
- edsair.doi.dedup.....fece0f10062f33bbf928651f93096ed7