Abstract
Proteasome inhibitors are an important part of our chemotherapeutic armamentarium against multiple myeloma, but the vast majority of patients eventually develop drug-resistant disease through incompletely understood mechanisms. Comparison of gene expression profiles (GEPs) of bortezomib-resistant (BR) myeloma cell lines with their drug-naïve counterparts revealed decreased expression of truncated Protein tyrosine phosphatase receptor-type O (PTPROt) in BR cells. Over-expression of wild-type PTPROt in drug-naïve and BR cells reduced myeloma cell proliferation, induced apoptosis, and sensitized cells to bortezomib and to alkylating agents. PTPROt expression reduced AKT phosphorylation and activity, and sensitized to pharmacologic AKT pathway inhibitors, but this was not the case for a substrate-trapping catalytic domain-inactivating mutant. Co-immunoprecipitation and mass spectrometry studies identified IQ motif containing GTPase activating protein 1 (IQGAP1) as a PTPROt binding partner, and PTPROt reduced tyrosine phosphorylation of IQGAP1, providing a link to AKT activity. Analysis of clinically annotated GEP databases identified high PTPROt expression as being related to an increased likelihood of achieving complete remission with bortezomib therapy, while low expression was linked to a greater likelihood of disease progression. Finally, high PTPROt expression associated with prolonged median overall survival in patients receiving bortezomib-based therapy in the front-line or relapsed and/or refractory settings. Taken together, these data identify PTPROt suppression as a novel mechanism of myeloma resistance to bortezomib in myeloma cell lines, and also support the possibility that PTPROt expression could be used as a biomarker to predict outcomes with bortezomib, and by which to select patients for therapy with AKT inhibitors.
Highlights
Multiple myeloma is a malignancy characterized by proliferation of clonal plasma cells and is the second most commonly diagnosed hematologic malignancy [1]
Its levels are decreased in germinal center-derived lymphomas, in which exogenous Protein tyrosine phosphatase receptor-type O (PTPROt) expression induced G0/G1 cell cycle arrest, indicating its role in the growth control of B-cells [22]. This may occur in part through the ability of PTPROt to dephosphorylate the Spleen tyrosine kinase SYK, producing an effect on tonic B-cell receptor (BCR) signaling [23]
PTPROt may itself be a target for repression by BCL6 as the latter modulates tonic BCR signaling in diffuse large B-cell lymphoma [36]
Summary
Multiple myeloma is a malignancy characterized by proliferation of clonal plasma cells and is the second most commonly diagnosed hematologic malignancy [1]. Studies based on pre-clinical models described a role in resistance for bortezomib binding pocket mutations in the β5 proteasome subunit [11,12,13] These mutations were later found to be absent from primary patient samples [14, 15], suggesting that they are not physiologically relevant. A more recent study utilizing both pre-clinical models and clinical data demonstrated the emergence of plasmablasts with reduced immunoglobulin production as another potential mechanism [16]. This would predict that all bortezomib-resistant patients should have nonsecretory myeloma, and while this can be seen [17], it occurs in only a small fraction of patients. Other mechanisms must contribute to acquired, or secondary resistance, as well as to primary, or de novo bortezomib resistance, which is demonstrated by the fact that the response rate in proteasome inhibitor-naive patients in the relapsed/refractory setting is under 50% [18, 19]
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