MEK inhibitor: the MM magic bullet?

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-γ-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.

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.