The Ras/Raf/MEK/extracellular signal regulated kinase (ERK) (Ras/mitogen-activated protein kinases (MAPK)) signal transduction pathway is a crucial mediator of many fundamental biological processes, including cellular proliferation, survival, angiogenesis and migration. Aberrant signalling through the Ras/MAPK cascade is common in a wide array of malignancies, including multiple myeloma (MM), making it an appealing candidate for the development of novel targeted therapies. In this review, we explore our current understanding of the Ras/MAPK pathway and its role in MM. Additionally, we summarise the current status of small molecule inhibitors of MEK under clinical evaluation, and discuss future approaches required to optimise their use.

Multiple myeloma continues to be a challenging disorder to treat despite improved therapies and the widespread use of proteasome inhibitors and immunomodulatory drugs. Although patient outcomes have improved, the disease continues to invariably relapse, and in the majority of cases, a cure remains elusive. In the last decade, there has been an explosion of novel drugs targeting cellular proteins essential for malignant plasma cell proliferation and survival. In this review, we focus on novel druggable targets leading to the development of monoclonal antibodies and cellular therapies against surface antigens (CD38, CD47, CD138, BCMA, SLAMF7, GPRC5D, FcRH5), inhibitors of epigenetic regulators such as histone deacetylase (HDAC), and agents targeting anti-apoptotic (BCL-2), ribosomal (eEF1A2) and nuclear export (XPO1) proteins.

Improved therapeutic interventions over the past decade has led to prolonged survival rates of patients with multiple myeloma (MM) but unfortunately, the subsequent development of progressive disease is inevitable. As such, the identification of novel compounds and strategies that improve therapeutic response is essential. GSK1120212b, a novel orally bio-available MEK inhibitor, has been shown to inhibit tumour growth and induce cell cycle arrest in some cancer cells. Here we report the efficacy of GSK1120212b in human myeloma cell lines (HMCL) and primary myeloma cells when used as a single agent and in combination with conventional and novel anti-myeloma therapies. HMCL response to variable doses of GSK1120212b (10nM-5µM) was determined by MTS assay. FACS and cell cycle analysis were used to evaluate the profiles of the cells post-MEK inhibition. Mechanistic studies using Western analysis with antibodies against p-MEK, MEK, p-ERK and ERK were performed. Subsequently, the anti-MM activity of GSK1120212b was evaluated in HMCL co-cultured with the human stromal cell line HS5. Primary samples from relapsed/refractory MM patients were subjected to GSK1120212b treatment and the level of apoptosis in CD45negCD38pos myeloma cells was assessed by Apo2.7-PE. Finally, combination studies with conventional and novel anti-MM therapies were also performed. GSK1120212b demonstrated an IC50 of 10-5000nM against 3 HMCL at 72h hours. Induction of both apoptosis and accumulation of cells in the G0/G1 phase occurred in a dose dependent manner. Western Blot analysis revealed increased p-MEK activity while total MEK levels decreased. Moreover, a decrease in p-ERK was observed with no change in total ERK levels. GSK1120212b demonstrated variable ability to induce HMCL apoptosis in stromal cell (HS5) co-culture, with or without transwells. Finally, GSK1120212b exhibited synergism with a variety of conventional and novel anti-MM therapies but was most pronounced when used in combination with GSK2110183b (Akt inhibitor) or LBH589 (HDAC inhibitor). Considering the potent anti-MM effects of GSK1120212b and its ability to synergise with other anti-MM agents, MEK inhibition demonstrates a promising future avenue for the management of MM and warrants further investigation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4579. doi:1538-7445.AM2012-4579

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