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Blood, 1 September 2007, Vol. 110, No. 5, pp. 1656-1663.
Prepublished online as a Blood First Edition Paper on May 17, 2007; DOI 10.1182/blood-2007-03-081240.
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Submitted March 21, 2007
Accepted May 15, 2007
Targeting MEK induces myeloma cell cytotoxicity and
inhibits osteoclastogenesis
Yu-Tzu Tai*, Mariateresa Fulciniti, Teru Hideshima, Weihua Song, Merav Leiba, Xian-Feng Li, Matthew Rumizen, Peter Burger, Aileen Morrison, Klaus Podar, Dharminder Chauhan, Pierfrancesco Tassone, Paul Richardson, Nikhil C Munshi, Irene Ghobrial, and Kenneth C Anderson
The Jerome Lipper Multiple Myeloma Center, Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States
Veterans Administration Boston Health Care System, Harvard Medical School, Boston, MA, United States
* Corresponding author; email: yu-tzu_tai{at}dfci.harvard.edu.
Activation of the extracellular signal-regulated kinase1/2 (ERK1/2) signaling cascade mediates human multiple myeloma (MM) growth and survival triggered by cytokines and adhesion to bone marrow stromal cells (BMSCs). Here, we examined the effect of AZD6244 (ARRY-142886), a novel and specific MEK1/2 inhibitor, on human MM cell growth in the bone marrow (BM) milieu. AZD6244 blocks constitutive and cytokine-stimulated ERK1/2 phosphorylation and inhibits proliferation and survival of human MM cell lines and patient MM cells, regardless of sensitivity to conventional chemotherapy. Importantly, AZD6244 (200 nM) induces apoptosis in patient MM cells even in the presence of exogenous interleukin-6 or BMSCs associated with triggering of caspase 3 activity. AZD6244 sensitizes MM cells to both conventional (dexamethasone) and novel (perifosine, lenalidomide, and bortezomib) therapies. AZD6244 downregulates the expression/secretion of osteoclast (OC)-activating factors from MM cells, and inhibits in vitro differentiation of MM patient PBMCs to OCs induced by ligand for receptor activator of NF- B (RANKL) and macrophage-colony stimulating factor (M-CSF). Finally, AZD6244 inhibits tumor growth and prolongs survival in vivo in a human plasmacytoma xenograft model. Taken together, these results show that AZD6244 targets both MM cells and OCs in the BM microenvironment, providing the preclinical framework for clinical trials to improve patient outcome in MM.
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