Impact of proteostasis workload on sensitivity to proteasome inhibitors in multiple myeloma

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F25%3A00635878" target="_blank" >RIV/61388963:_____/25:00635878 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00216208:11310/25:10498296

Výsledek na webu

<a href="https://doi.org/10.1007/s10238-025-01713-z" target="_blank" >https://doi.org/10.1007/s10238-025-01713-z</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1007/s10238-025-01713-z" target="_blank" >10.1007/s10238-025-01713-z</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Impact of proteostasis workload on sensitivity to proteasome inhibitors in multiple myeloma

Popis výsledku v původním jazyce

Genomic alterations and enormous monoclonal immunoglobulin production cause multiple myeloma to heavily depend on proteostasis mechanisms, including protein folding and degradation. These findings support the use of proteasome inhibitors for treating multiple myeloma and mantle cell lymphoma. Myeloma treatment has evolved, especially with the availability of new drugs, such as proteasome inhibitors, into therapeutic strategies for both frontline and relapsed/refractory disease settings. However, proteasome inhibitors are generally not effective enough to cure most patients. Natural resistance and eventual acquired resistance led to relapsed/refractory disease and poor prognosis. Advances in the understanding of cellular proteostasis and the development of innovative drugs that also target other proteostasis network components offer opportunities to exploit the intrinsic vulnerability of myeloma cells. This review outlines recent findings on the molecular mechanisms regulating cellular proteostasis pathways, as well as resistance, sensitivity, and escape strategies developed against proteasome inhibitors and provides a rationale and examples for novel combinations of proteasome inhibitors with FDA-approved drugs and investigational drugs targeting the NRF1 (NFE2L1)-mediated proteasome bounce-back response, redox homeostasis, heat shock response, unfolding protein response, autophagy, and VCP/p97 to increase proteotoxic stress, which can improve the efficacy of antimyeloma therapy based on proteasome inhibitors.

Název v anglickém jazyce

Impact of proteostasis workload on sensitivity to proteasome inhibitors in multiple myeloma

Popis výsledku anglicky

Genomic alterations and enormous monoclonal immunoglobulin production cause multiple myeloma to heavily depend on proteostasis mechanisms, including protein folding and degradation. These findings support the use of proteasome inhibitors for treating multiple myeloma and mantle cell lymphoma. Myeloma treatment has evolved, especially with the availability of new drugs, such as proteasome inhibitors, into therapeutic strategies for both frontline and relapsed/refractory disease settings. However, proteasome inhibitors are generally not effective enough to cure most patients. Natural resistance and eventual acquired resistance led to relapsed/refractory disease and poor prognosis. Advances in the understanding of cellular proteostasis and the development of innovative drugs that also target other proteostasis network components offer opportunities to exploit the intrinsic vulnerability of myeloma cells. This review outlines recent findings on the molecular mechanisms regulating cellular proteostasis pathways, as well as resistance, sensitivity, and escape strategies developed against proteasome inhibitors and provides a rationale and examples for novel combinations of proteasome inhibitors with FDA-approved drugs and investigational drugs targeting the NRF1 (NFE2L1)-mediated proteasome bounce-back response, redox homeostasis, heat shock response, unfolding protein response, autophagy, and VCP/p97 to increase proteotoxic stress, which can improve the efficacy of antimyeloma therapy based on proteasome inhibitors.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2025

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

CLINICAL AND EXPERIMENTAL MEDICINE

ISSN

1591-8890

e-ISSN

1591-9528

Svazek periodika

25

Číslo periodika v rámci svazku

1

Stát vydavatele periodika

IT - Italská republika

Počet stran výsledku

21

Strana od-do

176

Kód UT WoS článku

001495322000002

EID výsledku v databázi Scopus

2-s2.0-105006451879