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

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...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Michael F. Emmons, Nagaraju Anreddy, Javier Cuevas, Kayla Steinberger, Shengyu Yang, Mark McLaughlin, Ariosto Silva, Lori A. Hazlehurst
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/1cc53c35c5ad47088696b074a09dc978
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:1cc53c35c5ad47088696b074a09dc978
record_format	dspace
spelling	oai:doaj.org-article:1cc53c35c5ad47088696b074a09dc9782021-12-02T11:40:13ZMTI-101 treatment inducing activation of Stim1 and TRPC1 expression is a determinant of response in multiple myeloma10.1038/s41598-017-02713-02045-2322https://doaj.org/article/1cc53c35c5ad47088696b074a09dc9782017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-02713-0https://doaj.org/toc/2045-2322Abstract 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.Michael F. EmmonsNagaraju AnreddyJavier CuevasKayla SteinbergerShengyu YangMark McLaughlinAriosto SilvaLori A. HazlehurstNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-12 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Michael F. Emmons Nagaraju Anreddy Javier Cuevas Kayla Steinberger Shengyu Yang Mark McLaughlin Ariosto Silva Lori A. Hazlehurst MTI-101 treatment inducing activation of Stim1 and TRPC1 expression is a determinant of response in multiple myeloma
description	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.
format	article
author	Michael F. Emmons Nagaraju Anreddy Javier Cuevas Kayla Steinberger Shengyu Yang Mark McLaughlin Ariosto Silva Lori A. Hazlehurst
author_facet	Michael F. Emmons Nagaraju Anreddy Javier Cuevas Kayla Steinberger Shengyu Yang Mark McLaughlin Ariosto Silva Lori A. Hazlehurst
author_sort	Michael F. Emmons
title	MTI-101 treatment inducing activation of Stim1 and TRPC1 expression is a determinant of response in multiple myeloma
title_short	MTI-101 treatment inducing activation of Stim1 and TRPC1 expression is a determinant of response in multiple myeloma
title_full	MTI-101 treatment inducing activation of Stim1 and TRPC1 expression is a determinant of response in multiple myeloma
title_fullStr	MTI-101 treatment inducing activation of Stim1 and TRPC1 expression is a determinant of response in multiple myeloma
title_full_unstemmed	MTI-101 treatment inducing activation of Stim1 and TRPC1 expression is a determinant of response in multiple myeloma
title_sort	mti-101 treatment inducing activation of stim1 and trpc1 expression is a determinant of response in multiple myeloma
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/1cc53c35c5ad47088696b074a09dc978
work_keys_str_mv	AT michaelfemmons mti101treatmentinducingactivationofstim1andtrpc1expressionisadeterminantofresponseinmultiplemyeloma AT nagarajuanreddy mti101treatmentinducingactivationofstim1andtrpc1expressionisadeterminantofresponseinmultiplemyeloma AT javiercuevas mti101treatmentinducingactivationofstim1andtrpc1expressionisadeterminantofresponseinmultiplemyeloma AT kaylasteinberger mti101treatmentinducingactivationofstim1andtrpc1expressionisadeterminantofresponseinmultiplemyeloma AT shengyuyang mti101treatmentinducingactivationofstim1andtrpc1expressionisadeterminantofresponseinmultiplemyeloma AT markmclaughlin mti101treatmentinducingactivationofstim1andtrpc1expressionisadeterminantofresponseinmultiplemyeloma AT ariostosilva mti101treatmentinducingactivationofstim1andtrpc1expressionisadeterminantofresponseinmultiplemyeloma AT loriahazlehurst mti101treatmentinducingactivationofstim1andtrpc1expressionisadeterminantofresponseinmultiplemyeloma
_version_	1718395688849506304

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

Ejemplares similares