Novel targeting of phospho-cMET overcomes drug resistance and induces anti-tumor activity in multiple myeloma
Menée sur des lignées cellulaires et à l'aide de xénogreffes, cette étude évalue l'activité antitumorale d'un composé appelé SU1124, ciblant la signalisation cMET, pour le traitement d'un myélome multiple
Purpose: aim of the study was to verify the hypothesis that the cMET oncogene is implicated in chemio- and novel drug- resistance in MM. Experimental Design: we have evaluated the expression levels of cMET/p-cMET and the activity of the novel selective p-cMET inhibitor (SU11274) in MM cells, either sensitive (RPMI8226 and MM.1S) or resistant (R5 and MM.1R) to anti-MM drugs, in primary PCs and in MM xenograft models. Results:we found that resistant R5 and MM1R 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 RPMI8226 cells displayed cMET-dependent activation of mitogen-activated protein kinase pathway. The cMET and p-cMET expression was higher on PCs from MM patients at relapse or on drug-resistance than on those from patients at diagnosis, at complete/partial remission, or from patients with MGUS. Viability, chemotaxis, adhesion to fibronectin or paired BMSCs of PCs from relapsed or resistant patients was markedly inhibited by SU11274. Importantly SU11274 showed higher therapeutic activity in R5- than in RPMI8226-induced plasmocytomas. In R5 tumors, it caused apoptosis and necrosis, and reverted bortezomib resistance. Conclusions:Our findings suggest that the cMET pathway is constitutively activated in relapsed and resistant MM, where it may also be responsible for induction of drug resistance, thus providing the preclinical rationale for targeting cMET in relapsed/refractory MM patients.