Resensitising proteasome inhibitor-resistant myeloma with sphingosine kinase 2 inhibition

The introduction of the proteasome inhibitor bortezomib into treatment regimens for myeloma has led to substantial improvement in patient survival. However, whilst bortezomib elicits initial responses in many myeloma patients, this haematological malignancy remains incurable due to the development o...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Melissa K. Bennett, Manjun Li, Melinda N. Tea, Melissa R. Pitman, John Toubia, Paul P.-S. Wang, Dovile Anderson, Darren J. Creek, Robert Z. Orlowski, Briony L. Gliddon, Jason A. Powell, Craig T. Wallington-Beddoe, Stuart M. Pitson
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2022
Materias:	Myeloma Bortezomib Resistance Sphingolipid Unfolded protein response Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/f5e0bdd9d3004cfdbf70bbe296a47fe3
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:f5e0bdd9d3004cfdbf70bbe296a47fe3
record_format	dspace
spelling	oai:doaj.org-article:f5e0bdd9d3004cfdbf70bbe296a47fe32021-11-26T04:24:55ZResensitising proteasome inhibitor-resistant myeloma with sphingosine kinase 2 inhibition1476-558610.1016/j.neo.2021.11.009https://doaj.org/article/f5e0bdd9d3004cfdbf70bbe296a47fe32022-01-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S1476558621000993https://doaj.org/toc/1476-5586The introduction of the proteasome inhibitor bortezomib into treatment regimens for myeloma has led to substantial improvement in patient survival. However, whilst bortezomib elicits initial responses in many myeloma patients, this haematological malignancy remains incurable due to the development of acquired bortezomib resistance. With other patients presenting with disease that is intrinsically bortezomib resistant, it is clear that new therapeutic approaches are desperately required to target bortezomib-resistant myeloma. We have previously shown that targeting sphingolipid metabolism with the sphingosine kinase 2 (SK2) inhibitor K145 in combination with bortezomib induces synergistic death of bortezomib-naïve myeloma. In the current study, we have demonstrated that targeting sphingolipid metabolism with K145 synergises with bortezomib and effectively resensitises bortezomib-resistant myeloma to this proteasome inhibitor. Notably, these effects were dependent on enhanced activation of the unfolded protein response, and were observed in numerous separate myeloma models that appear to have different mechanisms of bortezomib resistance, including a new bortezomib-resistant myeloma model we describe which possesses a clinically relevant proteasome mutation. Furthermore, K145 also displayed synergy with the next-generation proteasome inhibitor carfilzomib in bortezomib-resistant and carfilzomib-resistant myeloma cells. Together, these findings indicate that targeting sphingolipid metabolism via SK2 inhibition may be effective in combination with a broad spectrum of proteasome inhibitors in the proteasome inhibitor resistant setting, and is an approach worth clinical exploration.Melissa K. BennettManjun LiMelinda N. TeaMelissa R. PitmanJohn ToubiaPaul P.-S. WangDovile AndersonDarren J. CreekRobert Z. OrlowskiBriony L. GliddonJason A. PowellCraig T. Wallington-BeddoeStuart M. PitsonElsevierarticleMyelomaBortezomibResistanceSphingolipidUnfolded protein responseNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENNeoplasia: An International Journal for Oncology Research, Vol 24, Iss 1, Pp 1-11 (2022)
institution	DOAJ
collection	DOAJ
language	EN
topic	Myeloma Bortezomib Resistance Sphingolipid Unfolded protein response Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Myeloma Bortezomib Resistance Sphingolipid Unfolded protein response Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Melissa K. Bennett Manjun Li Melinda N. Tea Melissa R. Pitman John Toubia Paul P.-S. Wang Dovile Anderson Darren J. Creek Robert Z. Orlowski Briony L. Gliddon Jason A. Powell Craig T. Wallington-Beddoe Stuart M. Pitson Resensitising proteasome inhibitor-resistant myeloma with sphingosine kinase 2 inhibition
description	The introduction of the proteasome inhibitor bortezomib into treatment regimens for myeloma has led to substantial improvement in patient survival. However, whilst bortezomib elicits initial responses in many myeloma patients, this haematological malignancy remains incurable due to the development of acquired bortezomib resistance. With other patients presenting with disease that is intrinsically bortezomib resistant, it is clear that new therapeutic approaches are desperately required to target bortezomib-resistant myeloma. We have previously shown that targeting sphingolipid metabolism with the sphingosine kinase 2 (SK2) inhibitor K145 in combination with bortezomib induces synergistic death of bortezomib-naïve myeloma. In the current study, we have demonstrated that targeting sphingolipid metabolism with K145 synergises with bortezomib and effectively resensitises bortezomib-resistant myeloma to this proteasome inhibitor. Notably, these effects were dependent on enhanced activation of the unfolded protein response, and were observed in numerous separate myeloma models that appear to have different mechanisms of bortezomib resistance, including a new bortezomib-resistant myeloma model we describe which possesses a clinically relevant proteasome mutation. Furthermore, K145 also displayed synergy with the next-generation proteasome inhibitor carfilzomib in bortezomib-resistant and carfilzomib-resistant myeloma cells. Together, these findings indicate that targeting sphingolipid metabolism via SK2 inhibition may be effective in combination with a broad spectrum of proteasome inhibitors in the proteasome inhibitor resistant setting, and is an approach worth clinical exploration.
format	article
author	Melissa K. Bennett Manjun Li Melinda N. Tea Melissa R. Pitman John Toubia Paul P.-S. Wang Dovile Anderson Darren J. Creek Robert Z. Orlowski Briony L. Gliddon Jason A. Powell Craig T. Wallington-Beddoe Stuart M. Pitson
author_facet	Melissa K. Bennett Manjun Li Melinda N. Tea Melissa R. Pitman John Toubia Paul P.-S. Wang Dovile Anderson Darren J. Creek Robert Z. Orlowski Briony L. Gliddon Jason A. Powell Craig T. Wallington-Beddoe Stuart M. Pitson
author_sort	Melissa K. Bennett
title	Resensitising proteasome inhibitor-resistant myeloma with sphingosine kinase 2 inhibition
title_short	Resensitising proteasome inhibitor-resistant myeloma with sphingosine kinase 2 inhibition
title_full	Resensitising proteasome inhibitor-resistant myeloma with sphingosine kinase 2 inhibition
title_fullStr	Resensitising proteasome inhibitor-resistant myeloma with sphingosine kinase 2 inhibition
title_full_unstemmed	Resensitising proteasome inhibitor-resistant myeloma with sphingosine kinase 2 inhibition
title_sort	resensitising proteasome inhibitor-resistant myeloma with sphingosine kinase 2 inhibition
publisher	Elsevier
publishDate	2022
url	https://doaj.org/article/f5e0bdd9d3004cfdbf70bbe296a47fe3
work_keys_str_mv	AT melissakbennett resensitisingproteasomeinhibitorresistantmyelomawithsphingosinekinase2inhibition AT manjunli resensitisingproteasomeinhibitorresistantmyelomawithsphingosinekinase2inhibition AT melindantea resensitisingproteasomeinhibitorresistantmyelomawithsphingosinekinase2inhibition AT melissarpitman resensitisingproteasomeinhibitorresistantmyelomawithsphingosinekinase2inhibition AT johntoubia resensitisingproteasomeinhibitorresistantmyelomawithsphingosinekinase2inhibition AT paulpswang resensitisingproteasomeinhibitorresistantmyelomawithsphingosinekinase2inhibition AT dovileanderson resensitisingproteasomeinhibitorresistantmyelomawithsphingosinekinase2inhibition AT darrenjcreek resensitisingproteasomeinhibitorresistantmyelomawithsphingosinekinase2inhibition AT robertzorlowski resensitisingproteasomeinhibitorresistantmyelomawithsphingosinekinase2inhibition AT brionylgliddon resensitisingproteasomeinhibitorresistantmyelomawithsphingosinekinase2inhibition AT jasonapowell resensitisingproteasomeinhibitorresistantmyelomawithsphingosinekinase2inhibition AT craigtwallingtonbeddoe resensitisingproteasomeinhibitorresistantmyelomawithsphingosinekinase2inhibition AT stuartmpitson resensitisingproteasomeinhibitorresistantmyelomawithsphingosinekinase2inhibition
_version_	1718409940814528512

Resensitising proteasome inhibitor-resistant myeloma with sphingosine kinase 2 inhibition

Ejemplares similares