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Sci Rep. 2017 Jun 2;7(1):2685. doi: 10.1038/s41598-017-02713-0.

MTI-101 treatment inducing activation of Stim1 and TRPC1 expression is a determinant of response in multiple myeloma.

Author information

1
Tumor Biology Department, Chemical Biology and Molecular Medicine Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA.
2
Modulation Therapeutics, Inc., 3802 Spectrum Boulevard, Suite 124, Tampa, FL, 33620, USA.
3
Department of Pharmaceutical Science, University of West Virginia, Morgantown, WV, 26506, USA.
4
Pharmacology and Physiology Department, University of South Florida, Tampa, FL, 33620, USA.
5
Department of Cancer Imaging and Metabolism, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA.
6
Department of Pharmaceutical Science, University of West Virginia, Morgantown, WV, 26506, USA. Lahazlehurst@hsc.wvu.edu.

Abstract

The emergence of drug resistance continues to be a major hurdle towards improving patient outcomes for the treatment of Multiple Myeloma. MTI-101 is a first-in-class peptidomimetic that binds a CD44/ITGA4 containing complex and triggers necrotic cell death in multiple myeloma cell lines. In this report, we show that acquisition of resistance to MTI-101 correlates with changes in expression of genes predicted to attenuate Ca2+ flux. Consistent with the acquired resistant genotype, MTI-101 treatment induces a rapid and robust increase in intracellular Ca2+ levels in the parental cells; a finding that was attenuated in the acquired drug resistant cell line. Mechanistically, we show that pharmacological inhibition of store operated channels or reduction in the expression of a component of the store operated Ca2+ channel, TRPC1 blocks MTI-101 induced cell death. Importantly, MTI-101 is more potent in specimens obtained from relapsed myeloma patients, suggesting that relapse may occur at a cost for increased sensitivity to Ca2+ overload mediated cell death. Finally, we demonstrate that MTI-101 is synergistic when combined with bortezomib, using both myeloma cell lines and primary myeloma patient specimens. Together, these data continue to support the development of this novel class of compounds for the treatment of relapsed myeloma.

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