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

Kihyun Kim, Sun-Young Kong, Mariateresa Fulciniti, Xianfeng Li, Weihua Song, Sabikun Nahar, Peter Burger, Mathew J Rumizen, Klaus Podar, Dharminder Chauhan, Teru Hideshima, Nikhil C Munshi, Paul Richardson, Ann Clark, Janet Ogden, Andreas Goutopoulos, Luca Rastelli, Kenneth C Anderson, Yu-Tzu Tai

Research output: Journal article (peer-reviewed)Journal article

121 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)537-549
Number of pages13
JournalBritish Journal of Haematology
Volume149
Issue number4
DOIs
Publication statusPublished - May 2010
Externally publishedYes

Keywords

  • Animals
  • Antineoplastic Agents/pharmacology
  • Antineoplastic Combined Chemotherapy Protocols/pharmacology
  • Apoptosis/drug effects
  • Cell Death/drug effects
  • Dose-Response Relationship, Drug
  • Humans
  • MAP Kinase Kinase 1/antagonists & inhibitors
  • MAP Kinase Kinase 2/antagonists & inhibitors
  • MAP Kinase Signaling System/drug effects
  • Mice
  • Mice, SCID
  • Multiple Myeloma/drug therapy
  • Niacinamide/analogs & derivatives
  • Protein Kinase Inhibitors/pharmacology
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

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