Blockade of the MEK/ERK signalling cascade by AS703026, a novel selective MEK1/2 inhibitor, induces pleiotropic anti‐myeloma activity in vitro and in vivo

Abstract

Summary This study investigated the cytotoxicity and mechanism of action of AS703026, a novel, selective, orally bioavailable MEK1/2 inhibitor, in human multiple myeloma (MM). AS703026 inhibited growth and survival of MM cells and cytokine‐induced osteoclast differentiation more potently (9‐ to 10‐fold) than AZD6244. Inhibition of proliferation induced by AS703026 was mediated by G0‐G1 cell cycle arrest and was accompanied by reduction of MAF oncogene expression. AS703026 further induced apoptosis via caspase 3 and Poly ADP ribose polymerase (PARP) cleavage in MM cells, both in the presence or absence of bone marrow stromal cells (BMSCs). Importantly, AS703026 sensitized MM cells to a broad spectrum of conventional (dexamethasone, melphalan), novel or emerging (lenalidomide, perifosine, bortezomib, rapamycin) anti‐MM therapies. Significant tumour growth reduction in AS703026‐ vs. vehicle‐treated mice bearing H929 MM xenograft tumours correlated with downregulated pERK1/2, induced PARP cleavage, and decreased microvessels in vivo. Moreover, AS703026 (<200 nmol/l) was cytotoxic against the majority of tumour cells tested from patients with relapsed and refractory MM (84%), regardless of mutational status of RAS and BRAF genes. Importantly, BMSC‐induced viability of MM patient cells was similarly blocked within the same dose range. Our results therefore support clinical evaluation of AS703026, alone or in combination with other anti‐MM agents, to improve patient outcome.

Poly(ADP-ribose) polymerase family member 14 (PARP14) is a novel effector of the JNK2-dependent pro-survival signal in multiple myeloma

“…2,4,5 Among the signaling pathways involved in the regulation of cell survival are members of the mitogen-activated protein kinase (MAPK) family, which includes three members: extracellular-regulated kinase (ERK1/2), Jun N-terminal kinase (JNK) and p38-MAPK signaling. [6][7][8] While the functions of ERK1/2 and p38-MAPK in MM have been defined in recent studies, 9,10 the role of JNK in the pathogenesis of the disease is unclear.…”

Bruton tyrosine kinase inhibition is a novel therapeutic strategy targeting tumor in the bone marrow microenvironment in multiple myeloma

“…17,19,20 In vitro OC culture and determination of OC formation CD14 ϩ OC precursor cells were selected by monocyte-cell enrichment RS cocktail (StemCell Technologies) from peripheral blood mononuclear cells from normal donors or MM patients after informed consent. 17,20 They were seeded in 96-well plates at 5 ϫ 10 4 cells per well on plastic or 1.5 ϫ 10 5 cells per well on dentine discs with DMEM/10% FCS supplemented with RANKL (50 ng/mL; PeproTech) and M-CSF (25 ng/mL; PeproTech), in the presence of serial dilutions of PCI-32765 (0-10M; Pharmacyclics). OCs were identified by staining for tartrateresistant acid phosphatase activity (TRAP), according to the manufacturers' instructions (Sigma-Aldrich).…”

A mechanistic rationale for MEK inhibitor therapy in myeloma based on blockade of MAF oncogene expression

“…[8][9][10] A novel, potent inhibitor of MEK1/2 affected MAF protein levels in the MM cell line H929. 11 We now extend these findings to a larger panel of MM cell lines to investigate whether particular myeloma subtypes would be especially sensitive to MEK inhibition. The current study dissects the contribution of MEK/ERK/AP-1 signaling to the transcription of MAF in MM.…”

“…Other studies with MM cells have also found caspase 3-dependent apoptosis in MM cells after MEK inhibition. 11,28 It is possible that the G 1 arrest was seen predominantly in the K-RAS mutant cell lines that are dependent on MEK signaling, whereas the MAF-expressing cells are more driven to apoptosis. In our hands and others, MEK inhibition induced myeloma cell apoptosis despite the presence of supportive contact with bone marrow stromal cells.…”