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: Contribution to journalArticle

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 G 0-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 (US)
Pages (from-to)537-549
Number of pages13
JournalBritish journal of haematology
Volume149
Issue number4
DOIs
StatePublished - May 2010

Keywords

  • Bone marrow stromal cells (BMSCs)
  • MEK1/2 inhibitor
  • Multiple myeloma (MM)
  • Novel kinase inhibitor therapy

ASJC Scopus subject areas

  • Hematology

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    Kim, K., Kong, S. Y., Fulciniti, M., Li, X., Song, W., Nahar, S., Burger, P., Rumizen, M. J., Podar, K., Chauhan, D., Hideshima, T., Munshi, N. C., Richardson, P., Clark, A., Ogden, J., Goutopoulos, A., Rastelli, L., Anderson, K. C., & Tai, Y. T. (2010). 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. British journal of haematology, 149(4), 537-549. https://doi.org/10.1111/j.1365-2141.2010.08127.x