RESUMO
IRE1α (inositol requiring enzyme 1 alpha) is one of the main transducers of the unfolded protein response (UPR). IRE1α plays instrumental protumoral roles in several cancers, and high IRE1α activity has been associated with poorer prognoses. In this context, IRE1α has been identified as a potentially relevant therapeutic target. Pharmacological inhibition of IRE1α activity can be achieved by targeting either the kinase domain or the RNase domain. Herein, the recent advances in IRE1α pharmacological targeting is summarized. We describe the identification and optimization of IRE1α inhibitors as well as their mode of action and limitations as anticancer drugs. The potential pitfalls and challenges that could be faced in the clinic, and the opportunities that IRE1α modulating strategies may present are discussed.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Endorribonucleases/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Regulação Alostérica/efeitos dos fármacos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Estresse do Retículo Endoplasmático/genética , Endorribonucleases/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias/genética , Neoplasias/patologia , Domínios Proteicos/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Proteostase/efeitos dos fármacos , Proteostase/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Resposta a Proteínas não Dobradas/efeitos dos fármacos , Resposta a Proteínas não Dobradas/genéticaRESUMO
BACKGROUND: Mutations in CALR observed in myeloproliferative neoplasms (MPN) were recently shown to be pathogenic via their interaction with MPL and the subsequent activation of the Janus Kinase - Signal Transducer and Activator of Transcription (JAK-STAT) pathway. However, little is known on the impact of those variant CALR proteins on endoplasmic reticulum (ER) homeostasis. METHODS: The impact of the expression of Wild Type (WT) or mutant CALR on ER homeostasis was assessed by quantifying the expression level of Unfolded Protein Response (UPR) target genes, splicing of X-box Binding Protein 1 (XBP1), and the expression level of endogenous lectins. Pharmacological and molecular (siRNA) screens were used to identify mechanisms involved in CALR mutant proteins degradation. Coimmunoprecipitations were performed to define more precisely actors involved in CALR proteins disposal. RESULTS: We showed that the expression of CALR mutants alters neither ER homeostasis nor the sensitivity of hematopoietic cells towards ER stress-induced apoptosis. In contrast, the expression of CALR variants is generally low because of a combination of secretion and protein degradation mechanisms mostly mediated through the ER-Associated Degradation (ERAD)-proteasome pathway. Moreover, we identified a specific ERAD network involved in the degradation of CALR variants. CONCLUSIONS: We propose that this ERAD network could be considered as a potential therapeutic target for selectively inhibiting CALR mutant-dependent proliferation associated with MPN, and therefore attenuate the associated pathogenic outcomes.
