Epithelial Ovarian Cancer: searching for new modulators of drug resistance

Epithelial Ovarian Cancer (EOC) is the most lethal gynaecological malignancy due to the advanced stage at diagnosis and the development of drug-resistant recurrences after a good initial response to the therapy based on platinum drugs. Alterations of different cellular pathways, such as DNA repair, apoptosis and p53, have been identified as linked to the onset of platinum resistance in ovarian cancer. We performed a high-throughput shRNA-based screening to identify genes whose suppression enhanced cell sensitivity to platinum drug in different EOC cell lines (synthetic lethality). Bioinformatics analysis and a subsequent validation screening identified 8 genes possibly involved in platinum response. Our aim was to dissect the role of one of these genes, SGK2 (serum and glucocorticoid-regulated kinase 2), in the response to platinum in EOC cells. We observed that 1) SGK2 overexpression conferred an increased platinum resistance to EOC cells, that acquired also a higher in vitro and in vivo growth rate respect to the control, and 2) by means of the SGK2 dominant negative (SGK2T193A/S356A) construct we demonstrated that SGK2 kinase activity was necessary to protect from platinum-induced death. For this reason, we tested the SGK kinase inhibitor GSK650394, showing that it was able to increase platinum-induced death only in SGK2-expressing EOC cells. Upon GSK650394 treatment, SGK2-expressing cells showed an accumulation of cytoplasmic autophagic vacuoles and increased expression of p62 and LC3II/LC3I, two known autophagy markers, suggesting that it induced alterations in the autophagy pathway. Evaluating additional critical markers of autophagy and monitoring autophagic flux, we confirmed that SGK2 inhibition (by silencing or pharmacological inhibition with GSK650394) induced a block of autophagy, favouring the accumulation of autophagic vacuoles already fused with lysosomes, but inefficient in the degradation of cell debris. Overall we identified a new role for SGK2 in the regulation of autophagy that likely explains its role in the control of platinum response in EOC cells. Considering that induction of autophagy is an escaping mechanism by which EOC cells could overcome platinum-induced death, the combination of SGK2 inhibition and platinum might represent a promising strategy to improve the treatment of EOC patients.