Phospho-cMET Inhibition in Multiple Myeloma


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In a study reported in Clinical Cancer Research, Moschetta and colleagues characterized the involvement of the cMet oncogene in drug resistance and the activity of a novel selective inhibitor of cMET/phospho-cMET (SU11274) in multiple myeloma cells sensitive (RPMI-8226 and MM.1S) and resistant (R5 and MM.1R) to multiple myeloma drugs, primary plasma cells, and multiple myeloma xenograft models.

Resistant R5 and MM.1R cells exhibited higher cMET phosphorylation, leading to constitutive activation of cMET-dependent signaling pathways. R5 cells exhibited higher susceptibility to the effects of SU11274 in inhibiting viability, proliferation, chemotaxis, and adhesion and in promoting apoptosis.  

Role of SU11274

SU11274 was able to reverse drug resistance in R5 cells. R5 but not RPMI-8226 cells displayed cMET-dependent activation of the MAPK pathway.  cMET and phospho-cMET expression was higher on plasma cells from patients with multiple myeloma at relapse or with drug resistance than on those from patients at diagnosis or in complete/partial remission  or those  from patients with monoclonal gammopathy of unknown significance. 

SU11274 markedly inhibited viability, chemotaxis, adhesion to fibronectin or paired bone marrow stromal cells of plasma cells from relapsed or resistant patients. SU11274 showed higher therapeutic activity in R5- than in RPMI-8226-induced plasmocytomas. In R5 tumors, it caused apoptosis and necrosis and reversed bortezomib resistance. 

The investigators concluded: “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.” 

In a study reported in Clinical Cancer Research, Moschetta and colleagues characterized the involvement of the cMet oncogene in drug resistance and the activity of a novel selective inhibitor of cMET/phospho-cMET (SU11274) in multiple myeloma cells sensitive (RPMI-8226 and MM.1S) and resistant (R5 and MM.1R) to multiple myeloma drugs, primary plasma cells, and multiple myeloma xenograft models.

Resistant R5 and MM.1R cells exhibited higher cMET phosphorylation, leading to constitutive activation of cMET-dependent signaling pathways. R5 cells exhibited higher susceptibility to the effects of SU11274 in inhibiting viability, proliferation, chemotaxis, and adhesion and in promoting apoptosis.  

Role of SU11274

SU11274 was able to reverse drug resistance in R5 cells. R5 but not RPMI-8226 cells displayed cMET-dependent activation of the MAPK pathway.  cMET and phospho-cMET expression was higher on plasma cells from patients with multiple myeloma at relapse or with drug resistance than on those from patients at diagnosis or in complete/partial remission  or those  from patients with monoclonal gammopathy of unknown significance. 

SU11274 markedly inhibited viability, chemotaxis, adhesion to fibronectin or paired bone marrow stromal cells of plasma cells from relapsed or resistant patients. SU11274 showed higher therapeutic activity in R5- than in RPMI-8226-induced plasmocytomas. In R5 tumors, it caused apoptosis and necrosis and reversed bortezomib resistance. 

The investigators concluded: “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.” ■

Moschetta M, et al: Clin Cancer Res 19:4371-4382, 2013.



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