Abstract
The aim of the study was to verify the hypothesis that the cMet oncogene is implicated in chemio- and novel drug resistance in multiple myeloma. We have evaluated the expression levels of cMET/phospho-cMET (p-cMET) and the activity of the novel selective p-cMET inhibitor (SU11274) in multiple myeloma cells, either sensitive (RPMI-8226 and MM.1S) or resistant (R5 and MM.1R) to anti-multiple myeloma drugs, in primary plasma cells and in multiple myeloma xenograft models. We found that resistant R5 and MM.1R cells presented with higher cMET phosphorylation, thus leading to constitutive activation of cMET-dependent signaling pathways. R5 cells exhibited a higher susceptibility to the SU11274 inhibitory effects on viability, proliferation, chemotaxis, adhesion, and to its apoptogenic effects. SU11274 was able to revert drug resistance in R5 cells. R5 but not RPMI-8226 cells displayed cMET-dependent activation of mitogen-activated protein kinase pathway. The cMET and p-cMET expression was higher on plasma cells from patients with multiple myeloma at relapse or on drug resistance than on those from patients at diagnosis, complete/partial remission, or from patients with monoclonal gammopathy of unknown significance. Viability, chemotaxis, adhesion to fibronectin or paired bone marrow stromal cells of plasma cells from relapsed or resistant patients was markedly inhibited by SU11274. Importantly, SU11274 showed higher therapeutic activity in R5- than in RPMI-8226-induced plasmocytomas. In R5 tumors, it caused apoptosis and necrosis and reverted bortezomib resistance. Our findings suggest that the cMET pathway is constitutively activated in relapsed and resistant multiple myeloma where it may also be responsible for induction of drug resistance, thus providing the preclinical rationale for targeting cMET in patients with relapsed/refractory multiple myeloma.
Highlights
The hepatocyte growth factor (HGF) receptor cMET is an oncogene that mediates growth, invasion, and metastasis of several tumors, including breast [1], colorectal [2], and lung carcinoma [3], and promotes angiogenesis [4]
Brset and colleagues first described the significance of the cMET in the pathogenesis and progression of multiple myeloma [12], and observations have been extended to other hematologic tumors [13]
Expression of cMET and HGF was evaluated in multiple myeloma cell lines either sensitive (RPMI-8226) or multiresistant (R5) to anti–multiple myeloma drugs
Summary
The hepatocyte growth factor (HGF) receptor cMET is an oncogene that mediates growth, invasion, and metastasis of several tumors, including breast [1], colorectal [2], and lung carcinoma [3], and promotes angiogenesis [4]. Brset and colleagues first described the significance of the cMET in the pathogenesis and progression of multiple myeloma [12], and observations have been extended to other hematologic tumors [13]. Multiple myeloma plasma cells express cMET and often simultaneously HGF [14]. The cMET oncogene is implicated in tumorigenesis and chemoresistance, and it is implicated in the pathogenesis and progression of multiple myeloma. A novel selective c-MET inhibitor SU11274 was able to exert significant therapeutic activity in a multiple myeloma xenograft model. Our results offer a preclinical rationale for targeting this pathway in relapsed and refractory multiple myeloma
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