Novel targeting of phospho-cMET overcomes drug resistance and induces antitumor activity in multiple myeloma

Michele Moschetta, Antonio Basile, Arianna Ferrucci, Maria Antonia Frassanito, Luigia Rao, Roberto Ria, Antonio Giovanni Solimando, Nicola Giuliani, Angelina Boccarelli, Fabio Fumarola, Mauro Coluccia, Bernardo Rossini, Simona Ruggieri, Beatrice Nico, Eugenio Maiorano, Domenico Ribatti, Aldo M. Roccaro, Angelo Vacca

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: 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. Experimental Design: 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. Results: 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 bonemarrow stromal cells of plasma cells fromrelapsed 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. Conclusion: 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.

Original languageEnglish
Pages (from-to)4371-4382
Number of pages12
JournalClinical Cancer Research
Volume19
Issue number16
DOIs
Publication statusPublished - Aug 15 2013

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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