|
|
Blood, 1 September 2007, Vol. 110, No. 5, pp. 1402-1403.
 Previous Article | Table of Contents | Next Article 
NEOPLASIA
Comment on Tai et al, page 1656
MEK inhibitor: the MM magic bullet?
Bruno Quesnel
CENTRE HOSPITALIER ET UNIVERSITAIRE DE LILLE
MEK/ERK pathway activation in multiple myeloma (MM) is critical for cell growth and survival. Tai and colleagues have demonstrated that the MEK1/2 inhibitor AZD6244 targets both MM cells and osteoclasts.
The RAS/RAF/MEK/ERK pathway is activated in many types of cancer through various mechanisms, including Ras or Raf mutations and autocrine or paracrine activation of receptor tyrosine kinases (RTKs). This has led to the development of several targeted drugs, although success to date has been limited. In MM, MEK/ERK is activated by Ras mutations in 30% to 40% of patients, and more so in advanced stages of MM. MM is the prototype of malignancy, with cross-talk between MM cells and the microenvironment mediated through ERK phosphorylation via IL6, IGF-1, VEGF, BAFF, and APRIL binding to their respective receptors, as well as adhesion of MM cells to bone marrow stromal cells (BMSCs), which mediates ERK activation independently of IL6. The MEK/ERK pathway is also involved in signaling in osteoclasts. Recently, it has also been shown that the MER/ERK pathway mediates TLR- and IFN- -mediated expression of B7-H1 in MM plasma cells, leading to T-cell inhibition and immune escape.1 Thus, the MEK/ERK pathway appears as one of the most tempting targets for drug development to treat this disease. PD98059 and UO126, the 2 most commonly used MEK inhibitors in preclinical studies, are not suitable for use in humans. AZD6244, an orally administered and highly specific MEK inhibitor, does not perturbate ATP-binding but locks MEK in an inactive conformation, thus accounting for its drug selectivity.2 AZD6244 has now entered into several clinical trials in the treatment of solid tumors.
Tai and colleagues have analyzed the effect of AZD6244 on MM cells in the presence of BMSCs (see figure). Testing drug efficacy under culture conditions mimicking the bone marrow microenvironment is necessary because several signals that could be blocked by the investigated drugs may be rescued through cytokines or the adhesion of MM cells to BMSCs. AZD6244 seems to disrupt several of the most important signals involved in MM physiopathology. It induces apoptosis in patient MM cells even in presence of IL6 or BMSCs, and sensitizes MM cells to apoptosis induced by dexamethasone and other therapies. AZD6244 also targets the microenvironment through down-regulation of osteoclast-activating factors in MM cells and direct inhibition of osteoclast differentiation induced by RANK-L and M-CSF. AZD6244 also reduced tumor growth in a human plasmacytoma xenograft model. Thus, AZD6244 appears to be a network inhibitor.
View larger version (34K):
[in this window]
[in a new window]
|
AZD6244 blocks osteoclast formation and transcripts of osteoclast-stimulating factors in MM cells. *P < .05; **P < .005; data represent the mean of 3 experiments (± SE). See the complete figure in the article beginning onpage 1656.
|
|
Is it the magic bullet for treatment of MM? Other signaling pathways are involved in the pathogenesis of MM. In a previous report, Chatterjee et al3 observed that combined disruption of MEK/ERK and STAT3 was required to induce apoptosis of MM cells in the presence of BMSCs. Another potential limitation is the loss by MM cells of dependence on the microenvironment in advanced stages. The description of non-Raf mechanisms of Ras transduction also suggests possible redundancies that could affect the efficacy of MEK inhibitors. The efficacy of AZD6244 on MM cells with mutated Ras also needs to be confirmed on larger cohorts. Thus, it seems likely that this drug will be best used in combination with other therapies. Notwithstanding these remaining questions, network inhibition through MEK appears to be one of the most promising strategies in MM.
Footnotes
Conflict-of-interest disclosure: The author declares no competing financial interests. 
REFERENCES
- Liu J, Hamrouni A, Wolowiec D, et al. Plasma cells from multiple myeloma patients express B7-H1 (PD-L1) and increase expression following stimulation with IFN- and TLR ligands via a MyD88-, TRAF6-, and MEK-dependent pathway. Blood 2007; 110:296–304.[Abstract/Free Full Text]
- Roberts PJ and Der CJ. Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene 2007; 26:3291–3310.[CrossRef][Medline]
[Order article via Infotrieve]
- Chatterjee M, Stuhmer T, Herrmann P, Bommert K, Dorken B, Bargou RC. Combined disruption of both the MEK/ERK and the IL-6R/STAT3 pathways is required to induce apoptosis of multiple myeloma cells in the presence of bone marrow stromal cells. Blood 2004; 104:3712–3721.[Abstract/Free Full Text]
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
Related Article in Blood Online:
-
Targeting MEK induces myeloma-cell cytotoxicity and inhibits osteoclastogenesis
- Yu-Tzu Tai, Mariateresa Fulciniti, Teru Hideshima, Weihua Song, Merav Leiba, Xian-Feng Li, Matthew Rumizen, Peter Burger, Aileen Morrison, Klaus Podar, Dharminder Chauhan, Pierfrancesco Tassone, Paul Richardson, Nikhil C. Munshi, Irene M. Ghobrial, and Kenneth C. Anderson
Blood 2007 110: 1656-1663.
[Abstract]
[Full Text]
[PDF]
|
|
