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

Michael F. Emmons, Nagaraju Anreddy, Javier Cuevas, Kayla Steinberger, Shengyu Yang, Mark McLaughlin, Ariosto Silva, Lori A. Hazlehurst

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish (US)
Article number2685
JournalScientific reports
Volume7
Issue number1
DOIs
StatePublished - Dec 1 2017

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Multiple Myeloma
Cell Death
Cell Line
Therapeutics
Peptidomimetics
Drug Resistance
MTI-101
Genotype
Pharmacology
Gene Expression
Costs and Cost Analysis
Recurrence
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • General

Cite this

Emmons, Michael F. ; Anreddy, Nagaraju ; Cuevas, Javier ; Steinberger, Kayla ; Yang, Shengyu ; McLaughlin, Mark ; Silva, Ariosto ; Hazlehurst, Lori A. / MTI-101 treatment inducing activation of Stim1 and TRPC1 expression is a determinant of response in multiple myeloma. In: Scientific reports. 2017 ; Vol. 7, No. 1.
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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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Emmons, MF, Anreddy, N, Cuevas, J, Steinberger, K, Yang, S, McLaughlin, M, Silva, A & Hazlehurst, LA 2017, 'MTI-101 treatment inducing activation of Stim1 and TRPC1 expression is a determinant of response in multiple myeloma', Scientific reports, vol. 7, no. 1, 2685. https://doi.org/10.1038/s41598-017-02713-0

MTI-101 treatment inducing activation of Stim1 and TRPC1 expression is a determinant of response in multiple myeloma. / Emmons, Michael F.; Anreddy, Nagaraju; Cuevas, Javier; Steinberger, Kayla; Yang, Shengyu; McLaughlin, Mark; Silva, Ariosto; Hazlehurst, Lori A.

In: Scientific reports, Vol. 7, No. 1, 2685, 01.12.2017.

Research output: Contribution to journalArticle

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AU - Emmons, Michael F.

AU - Anreddy, Nagaraju

AU - Cuevas, Javier

AU - Steinberger, Kayla

AU - Yang, Shengyu

AU - McLaughlin, Mark

AU - Silva, Ariosto

AU - Hazlehurst, Lori A.

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N2 - 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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