Glucocorticoid resistance in multiple myeloma: A mechanistic study and new therapeutic targets

Le résumé fourni par la source

The treatment of newly diagnosed multiple myeloma (MM) patients typically consists of a multimodal approach, with glucocorticoids (GC) as a crucial treatment pillar in the diagnosis, but also relapsed settings. Despite a rapidly changing therapeutic armamentarium, the disease remains incurable as patients become therapy resistant to (a component of) the combination treatment. In this thesis, we used different in cellulo models of GC resistance to gain insights into the mechanistic processes of emerging GC therapy resistance. We demonstrate that partial resistance to GC-induced apoptosis is not associated with lower levels of the drug target itself, i.e. the glucocorticoid receptor (GR), but with a dampened GR-dependent transcriptional output. From these analyses, we validated a biomarker, CCR1 expressed on the myeloma cells, to have a pivotal role in determining the GC sensitivity of MM cells. We demonstrate that blocking CCR1 signalling enhances the cytotoxic effects of dexamethasone in MM cell lines, primary patient material and in a myeloma mouse model, where we also observed indications of improved MM bone disease with CCR1 inhibition. To conclude, this thesis delivers further insight into the mechanisms by which MM cells acquire resistance to GCs and our results add to the growing body of evidence that CCR1 targeting in MM therapy holds promise.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.