Chemoresistance in Epithelial Ovarian Cancer: in vitro selection and characterization of platinum resistant cells

Epithelial Ovarian Cancer (EOC) is the fifth leading cause of cancer death in women worldwide. Its high mortality rate is mainly due to late diagnosis, when tumors are spread out into the abdominal cavity. The standard care for patients combines radical surgery with platinum-taxol chemotherapy. Despite a good initial response, development of a platinum resistant disease is a frequent event in advanced EOC patients and predicts poor prognosis. Thus, improving response to platinum represent an unmet goal in EOC treatment. We have recently contributed to this issue reporting the molecular and biological characterization of three out of the seven new isogenic models of platinum resistant (PT-res) EOC cell lines we have generated in the lab: MDAH-2774, TOV-112D and OVSAHO. Our characterization pointed out a higher ability of the three isogenic PT-res cells to resolve PT-induced DNA damage, compared to parental cells, suggesting that drug uptake, detoxification and excretion, along with the DNA repair pathway, play a central role in the instauration of a resistant phenotype. Moreover, all PT-res cells displayed an evident change in their morphology, accompanied by higher ability to grow on mesothelium. This included a reorganization of cytoskeleton, cell-cell junctions and adhesion abilities. We went deeper in the biological and molecular characterization of MDAH-2774 PT-res cells reporting the appearance of a novel mutation (S185G), that accompanied the already present R273H, in TP53 gene. This additional mutation, likely induced by platinum, was associated with higher p53 phosphorylation on Ser37 that might confer increased activity to an already mutated TP53. Its expression had functional consequences, since it significantly increased PT-resistance in SKOV3 (p53NULL) cells and was associated with the higher PT-resistant phenotype in MDAH cells. Mechanistically, we hypothesized that the more active p53S185G/R273H protein, in MDAH cells, was at least partially responsible for an altered progression through the M phase of the cell cycle, that eventually results in deregulated mitosis with the appearance of a subpopulation of enlarged multinucleated cells (MNGCs). Indeed, TP53MUT specifically regulates the transcription of mitotic-regulator genes, supporting the possibility that it confers a surviving advantage to aberrant mitotic cells. Future studies are necessary to properly clarify the molecular mechanisms underlying the formation of MNGCs and how p53S185G/R273H contributes to this resistant phenotype.