Truncated protein tyrosine phosphatase receptor type O suppresses AKT signaling through IQ motif containing GTPase activating protein 1 and confers sensitivity to bortezomib in multiple myeloma
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Hua Wang1, Veerabhadran Baladandayuthapani2, Zhiqiang Wang1, Heather Lin2, Zuzana Berkova1, Richard E. Davis1, Lin Yang3 and Robert Z. Orlowski1,4
1Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
2Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
3Cyrus Tang Hematology Center, Soochow University, Suzhou, China
4Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Robert Z. Orlowski, email: [email protected]
Keywords: multiple myeloma; drug resistance; AKT; GTPase activating protein 1; tyrosine phosphatase
Received: September 04, 2017 Accepted: November 20, 2017 Published: December 07, 2017
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.
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