Targeting NF-{kappa}B in Waldenstrom macroglobulinemia.
Blood. 2008 Mar 11
Leleu X, Eeckhoute J, Jia X, Roccaro AM, Moreau AS, Farag M, Sacco A, Ngo HT, Runnels J, Melham MR, Burwick N, Azab A, Azab F, Hunter Z, Hatjiharissi E, Carrasco DR, Treon SP, Witzig TE, Hideshima T, Brown M, Anderson KC, Ghobrial IM.
Medical Oncology, Dana-Farber Cancer Institute, and Harvard Medical School, Boston, MA, United States.
The NF-kappaB pathway has been implicated in tumor B cell survival, growth and resistance to therapy. Because tumor cells overcome single agent antitumor activity, we hypothesized that combination of agents that target differentially NF-kappaB pathway will induce significant cytotoxicity. Therapeutic agents that target proteasome and Akt pathways should induce significant activity in B cell malignancies as both pathways impact NF-kappaB activity. We demonstrated that perifosine and bortezomib both targeted NF-kB through its recruitment to the promoter of its target gene IkB using chromatin immunoprecipitation (ChIP) assay. This combination led to synergistic cytotoxicity in Waldenstrom Macroglobulinemia (WM) cells that was mediated through a combined reduction of the PI3K/Akt and ERK signaling pathways, found to be critical for survival of WM cells. Moreover, combination of these drugs with the CD20 monoclonal antibody rituximab further increased their cytotoxic activity. Thus, effective WM therapy may require combination regimens targeting the NF-kappaB pathway. |
