RESUMEN
BACKGROUND: Primary mediastinal B-cell lymphoma (PMBL) and classical Hodgkin lymphoma (cHL) are distinct hematological malignancies of B-cell origin that share many biological, molecular, and clinical characteristics. In particular, the JAK/STAT signaling pathway is a driver of tumor development due to multiple recurrent mutations, particularly in STAT6. Furthermore, the XPO1 gene that encodes exportin 1 (XPO1) shows a frequent point mutation (E571K) resulting in an altered export of hundreds of cargo proteins, which may impact the success of future therapies in PMBL and cHL. Therefore, targeted therapies have been envisioned for these signaling pathways and mutations. METHODS: To identify novel molecular targets that could overcome the treatment resistance that occurs in PMBL and cHL patients, we have explored the efficacy of a first-in-class HSP110 inhibitor (iHSP110-33) alone and in combination with selinexor, a XPO1 specific inhibitor, both in vitro and in vivo. RESULTS: We show that iHSP110-33 decreased the survival of several PMBL and cHL cell lines and the size of tumor xenografts. We demonstrate that HSP110 is a cargo of XPO1wt as well as of XPO1E571K. Using immunoprecipitation, proximity ligation, thermophoresis and kinase assays, we showed that HSP110 directly interacts with STAT6 and favors its phosphorylation. The combination of iHSP110-33 and selinexor induces a synergistic reduction of STAT6 phosphorylation and of lymphoma cell growth in vitro and in vivo. In biopsies from PMBL patients, we show a correlation between HSP110 and STAT6 phosphorylation levels. CONCLUSIONS: These findings suggest that HSP110 could be proposed as a novel target in PMBL and cHL therapy.
Asunto(s)
Proteína Exportina 1 , Enfermedad de Hodgkin , Carioferinas , Receptores Citoplasmáticos y Nucleares , Humanos , Carioferinas/antagonistas & inhibidores , Carioferinas/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismo , Receptores Citoplasmáticos y Nucleares/antagonistas & inhibidores , Animales , Ratones , Enfermedad de Hodgkin/tratamiento farmacológico , Enfermedad de Hodgkin/patología , Enfermedad de Hodgkin/metabolismo , Enfermedad de Hodgkin/genética , Linfoma de Células B/tratamiento farmacológico , Linfoma de Células B/metabolismo , Linfoma de Células B/patología , Linfoma de Células B/genética , Proteínas del Choque Térmico HSP110/metabolismo , Proteínas del Choque Térmico HSP110/genética , Línea Celular Tumoral , Neoplasias del Mediastino/tratamiento farmacológico , Neoplasias del Mediastino/metabolismo , Neoplasias del Mediastino/patología , Neoplasias del Mediastino/genética , Ensayos Antitumor por Modelo de Xenoinjerto , Triazoles/farmacología , Triazoles/uso terapéutico , Hidrazinas/farmacología , Hidrazinas/uso terapéutico , Femenino , Factor de Transcripción STAT6/metabolismo , Terapia Molecular DirigidaRESUMEN
Heat-shock proteins (HSPs) are powerful chaperones that provide support for cellular functions under stress conditions but also for the homeostasis of basic cellular machinery. All cancer cells strongly rely on HSPs, as they must continuously adapt to internal but also microenvironmental stresses to survive. In solid tumors, HSPs have been described as helping to correct the folding of misfolded proteins, sustain oncogenic pathways, and prevent apoptosis. Leukemias and lymphomas also overexpress HSPs, which are frequently associated with resistance to therapy. HSPs have therefore been proposed as new therapeutic targets. Given the specific biology of hematological malignancies, it is essential to revise their role in this field, providing a more adaptable and comprehensive picture that would help design future clinical trials. To that end, this review will describe the different pathways and functions regulated by HSP27, HSP70, HSP90, and, not least, HSP110 in leukemias and lymphomas.