Abstract 1710: Bortezomib and lenalidomide resistant myeloma cells overexpress the hepatocyte growth factor/MET signaling axis and respond to MET kinase inhibitors
Authors: Zaman Shadia , Stellrecht Christine M. , Orlowski Robert Z. , Gandhi Varsha 
Published: May 2015

Multiple Myeloma (MM) is a plasma cell neoplasm that responds well to therapeutic agents such as bortezomib, a proteasome inhibitor, and lenalidomide, an immunomodulatory drug. However, myeloma patients acquire resistance to these agents and disease relapses. Previously, it has been established that levels of hepatocyte growth factor (HGF) are high in serum of myeloma patients. In concert, our studies in myeloma indicated that HGF gene expression is also high in CD138+ myeloma plasma cells. High HGF levels in serum and in myeloma cells are correlated with poor prognosis and advanced disease. HGF is the ligand for the MET receptor tyrosine kinase that controls proliferation, survival and migration. Our earlier studies demonstrated that MET acts as a survival factor in myeloma cells. We hypothesized that MET/HGF axis may serve as a resistant mechanism in myeloma. To test this, we examined the HGF/MET signaling pathway in bortezomib and lenalidomide resistant myeloma cell lines. These lines were developed by continuous exposure of cells to increasing concentrations of the respective drug. We used three paired cell lines; KAS-6/1 wild type (WT) and bortezomib resistant (KAS-6/V10R) as well as lenalidomide resistant (KAS-6/R10R); WT MM1.S and its lenalidomide resistant counterpart (MM1.R10R), and WT ANBL-6 and its bortezomib resistant (ANBL-6/V10R) pair. Compared to WT cells (KAS-6/1, MM.1S), resistant cell lines overexpress MET at both the protein and mRNA levels. MET is four-fold higher in KAS-6/V10R and KAS-6/R10R compared to KAS-6/1 at both the protein and mRNA level while it is three-fold higher in MM.1/R10R compared to MM.1S at the protein level. On the other hand, compared to WT ANBL-6 cells, the bortezomib resistant cell line ANBL-6/V10R does not overexpress MET but secretes higher (2.6x) levels of HGF into the medium. The overexpression of MET in the resistant cell lines is associated with increased signaling of the HGF/MET pathway at both basal conditions and upon HGF-stimulated activation of the HGF/MET pathway as we observed higher levels of phospho-AKT(S473), phospho-GSK3β(S9) and phospho-ERK1/2 in lenalidomide resistant cell lines compared to WT controls. To test utility of MET kinase inhibitors in bortezomib and lenalidomide resistant cell lines, we used crizotinib, SU11274, ARQ 197 and SGX523, all small-molecule MET kinase inhibitors. Our studies demonstrate that targeted MET kinase inhibition induced apoptosis with concomitant inhibition of growth in these resistant myeloma cell lines. Depending on the potency of the compound, we observed 1 - 90% apoptosis and 15 - 70 % growth inhibition with these inhibitors at 3 μM level. Taken together, out study implies that bortezomib and lenalidomide resistant myeloma may have active HGF/MET axis and MET inhibitors may have therapeutic efficacy for these patients.

Citation Format: Shadia Zaman, Christine M. Stellrecht, Robert Z. Orlowski, Varsha Gandhi. Bortezomib and lenalidomide resistant myeloma cells overexpress the hepatocyte growth factor/MET signaling axis and respond to MET kinase inhibitors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1710. doi:10.1158/1538-7445.AM2014-1710