Induction of endoplasmic reticulum stress by sorafenib and activation of NF-κB by lestaurtinib as a novel resistance mechanism in Hodgkin lymphoma cell lines

Menée sur des lignées cellulaires de lymphome hodgkinien classique, cette étude met en évidence l'activation de la signalisation NF-κB dans l'apparition d'une résistance à un inhibiteur de tyrosine kinase tel que le sorafenib ou le lestaurtinib

Résumé en anglais

Hodgkin-Reed/Sternberg (HRS) cells of classical Hodgkin lymphoman (HL) show aberrant expression and activation of several receptor tyrosine kinases (RTKs) in the majority of cases. Therefore we tested whether tyrosine kinase inhibitors (TKIs) already in clinical use or late stages of clinical trials have antiproliferative effects on HRS cell lines and evaluated the targets, affected signaling pathways and mechanisms of cell death and resistance. Sorafenib and lestaurtinib had antiproliferative effects on HRS cell lines at concentrations achievable in patients. Sorafenib inhibited PDGFRα, TRKA and RON, caused decreases in total and phosphorylated amounts of several signaling molecules and provoked Caspase 3 independent cell death, most likely due to endoplasmic reticulum stress as indicated by upregulation of GADD34 and GADD153 and phosphorylation of PERK. Lestaurtinib inhibited TRKA, PDGFRα, RON and JAK2 and had only a cytostatic effect. Besides deactivation lestaurtinib caused also activation of signaling pathways. It caused increases in CD30L and TRAIL expression, and CD30L/CD30 signaling likely led to the observed concomitant activation of ERK1/2 and the alternative NF-κB pathway. These data disclose the possible utility of sorafenib for the treatment of HL and highlight NF-κB activation as a potential novel mechanism of resistance towards tyrosine kinase inhibitors.