Fig. 5

Downregulation of MYPT1 increases resistance to platinum treatment by activating the Hippo pathway. a Determination of the IC50 for cis-platinum in combination or not with 2 nM of the YAP inhibitor verteporfin (YAPi) in ES-2, SKOV3 and OVCAR8 cells overexpressing shMYPT1, miR-30b or EV. b Quantification of the number and size of tumorspheres formed in the same cells and conditions than a. c Percentage of holoclones formed in the same cells and conditions than a. d Determination of the tumor volume (top) and survival (bottom) after treatment with cisplatin and/or 100 nM YAPi in xenografts of SKOV3 cells expressing shMYPT1 or EV. e Determination of the efficiency of tumor formation and size of xenografts from tumorspheres derived from SKOV3 and OVCAR8 cells expressing shMYPT1 or EV, treated with saline, cisplatin, 2 nM YAPi or both. f MYPT1 expression in the GSE63885 ovarian cancer patient database. Box plots showing the expression levels of MYPT1 in ovarian platinum-sensitive (S; pink) or platinum-resistant (R; green) patients. g Cumulative distribution of Pearson’s correlation with the Hippo pathway genes from GSE63885. h Analysis of the MYPT1 and miR-30b expression level by RT-qPCR in a cohort of ovarian cancer patients that were sensitive (S; pink) or resistant (R; green) to platinum treatment (HUVR-IBIS). See Additional file 1: Table S4. i Kaplan-Meier plots showing overall or progression-free survival in patients who were sensitive (pink) or resistant (green) to platinum treatment in the HUVR-IBIS cohort. j Proposed model for how MYPT1 loss induces resistance to treatment with platinum therapy. Briefly, MYPT1 absence leads to deactivation of the Hippo pathway, which in turn favors YAP activation and target gene expression of genes associated to tumor growth and stemness. This increased stemness would be responsible for therapy resistance due to the increase in the CSC population