Abstract B224: Multi-tyrosine kinase targeting resulting in concomitant downregulation of proliferation/survival pathways dependent on FGF-R3, Jak2 and BCMA in human multiple myeloma cells

Abstract

Abstract Proliferation/survival pathways constitutively activated by genetic alterations in multiple myeloma (MM), or sustained by the bone marrow (BM) microenvironment, provide opportunities for the development of novel targeted therapies. Deregulated protein tyrosine kinases (TKs) involved in these pathways may play a critical role in driving the MM malignant phenotype thus representing attractive therapeutic targets. We have investigated the effects of a multi-target tyrosine kinase inhibitor (1,3-dihydro-5,6-dimethoxy-3-[(4-hydrophenyl)methylene]1-indol-2-one) (named RPI-1 in our laboratory) in a panel of human MM cell lines, including t(4;14) positive cell lines expressing the TK receptor FGF-R3. Cells harboring FGF-R3 activating mutations (KMS11 and OPM2) displayed the highest sensitivity to the drug antiproliferative effect. However, proliferation induced by the FGF-R3 ligand, aFGF, was abrogated even in cells harboring a non-constitutively active receptor. Drug treatment inhibited activation and expression of the FGF-R3Y373C mutant as well as aFGF-dependent signaling involving AKT and ERKs. Jak2 has been identified as an additional target of RPI-1 in MM cells. Inhibition of Jak2 TK resulted in STAT3 inactivation. Blockade of these proliferation/survival pathways was associated with activation of caspase-dependent apoptosis. Moreover, the TK inhibitor abrogated proliferative and pro-invasive stimuli provided by conditioned medium from mesenchymal stromal cells. Gene expression analysis of KMS11 cells showed 22 upregulated and 52 downregulated genes upon RPI-1 treatment, with an early modulation of genes implicated in MM pathobiology such as SAT-1, MYC, MIP-1α/β, FGF-R3, and the growth factor receptor B-cell maturation antigen (BCMA). Thus, concomitant blockade of FGF-R3 and Jak2 results in inhibition of several MM-promoting pathways, including BCMA-regulated signaling, and downregulation of disease-associated proteins. Overall, these data support the therapeutic interest for FGF-R3/JAK2 multi-target approaches in the treatment of t(4;14) MM. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B224.