Fig. 1: Model depicting how platinum drug therapy resistance in solid cancers involves direct glucocorticoid receptor activation and subsequent MAST1 activation.

The intracellular pathway established specifically upon cisplatin-resistance and in presence of glucocorticoids is presented. Glucocorticoids (black circle) activate the glucocorticoid receptor (GR), an intracellular receptor that, when bound to ligand, can translocate to the nucleus (pathway on the right-hand side). There, the glucocorticoid receptor regulates its target genes via different mechanisms, directly or indirectly, and in a cell-type specific manner. Depicted are likely mechanisms, but alternative mechanisms are not excluded. Generally, pro-apoptotic gene expression (e.g. Bim), cell cycle arrest and anti-inflammatory gene expression are promoted, while pro-inflammatory (NF-kB-dependent) gene expression and anti-apoptotic gene expression are dampened. Besides glucocorticoid receptor monomer and dimer-driven mechanisms, also other mechanisms have been described to account for the indicated gene profiles (not depicted here). Cisplatin-resistance involves binding of cisplatin to the glucocorticoid receptor at Cystein 622, followed by its nuclear accumulation and its ability to enhance gene and protein expression of MAST1 (pathway on the left-hand side). On its turn, MAST1 can block the pro-apoptotic Bim, hereby establishing cisplatin-resistance. Addition of the MAST1 inhibitor Lestaurtinib relieves the brake on Bim and may restore sensitivity to platinum-based drugs. Lestaurtinib does not seem to affect the capacity of the glucocorticoid receptor to regulate other typical target genes, including those involved in the relief of side effects (not depicted here). Abbreviations: GR, glucocorticoid receptor, GRE, glucocorticoid response element, MAST1, microtubule-associated Ser/Thr kinase, TFRE, transcription factor response element.