TY - JOUR
T1 - Novel targeting of phospho-cMET overcomes drug resistance and induces antitumor activity in multiple myeloma
AU - Moschetta, Michele
AU - Basile, Antonio
AU - Ferrucci, Arianna
AU - Frassanito, Maria Antonia
AU - Rao, Luigia
AU - Ria, Roberto
AU - Solimando, Antonio Giovanni
AU - Giuliani, Nicola
AU - Boccarelli, Angelina
AU - Fumarola, Fabio
AU - Coluccia, Mauro
AU - Rossini, Bernardo
AU - Ruggieri, Simona
AU - Nico, Beatrice
AU - Maiorano, Eugenio
AU - Ribatti, Domenico
AU - Roccaro, Aldo M.
AU - Vacca, Angelo
PY - 2013/8/15
Y1 - 2013/8/15
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=84882986288&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-13-0039
DO - 10.1158/1078-0432.CCR-13-0039
M3 - Article
C2 - 23804425
AN - SCOPUS:84882986288
VL - 19
SP - 4371
EP - 4382
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 16
ER -