Molecular alterations chemoresistance-related in ovarian cancer patients and related target therapies

INTRODUCTION. Ovarian cancer has the highest rate of mortality among gynecological malignancies and it is the fifth leading cause of cancer-related death in women of developed countries. It is often diagnosed at late stage, therefore, despite optimal cytoreduction by debulking surgery and adjuvant chemotherapy, recurrence is frequent. New therapeutic strategies are needed to treat relapses and advanced stage chemoresistant ovarian cancer. Ovarian cancer is characterized by different molecular phenotypes, and it can be classified in five tumor types with different clinical, pathologic and prognostic properties, and with different chemosensitivity. OBJECTIVE. This review will focus on molecular alterations involved in ovarian cancer carcinogenesis, which may become new targets for therapy in the future. Biological therapies can impact on the prognosis, especially in advanced chemoresistant ovarian cancer patients. DISCUSSION. The most important pathways involved in ovarian cancer chemoresistance are PI3K/AKT/mTOR, KRAS/MAPK/ERK, BRCA1/BRCA2, Notch and Forkhead Box M1 pathways. The amplification of PI3K is more frequent in high-grade ovarian tumors rather than in low grade ones, together with AKT phosphorylation, contributing to disease progression. KRAS mutations are frequent in low-grade ovarian tumors, and their expression varies in different histopathological types. Loss of PTEN is frequently present in high-grade serous carcinomas and correlates with a poor prognosis. Several protein kinases and other signaling molecules, such as KRAS, BRAF, PI3KCA and CTNNB1, have been evaluated and their mutations have been correlated with prognosis. Epigenetic modifications are promising targets for ovarian cancer treatment. Several studies on molecular alterations have been conducted on ovarian cancer tissue, but further studies are needed to tailor every therapy to the specific histotype of ovarian cancer. Actually, the approved biological therapies currently used in ovarian cancer patients are only three: Bevacizumab (a monoclonal antibodies directed against VEGF, usually utilized in platinum-pretreated patients), Pazopanib (tyrosine kinase inhibitor) and Olaparib (PARP-inhibitor, utilized in BRCA1/2 mutated patients). Further studies are needed to better evaluate different chemoresistance related pathways, and to find new targets on which to focus clinical research. CONCLUSIONS. Among the analyzed studies, only molecular alterations of PI3KI seem to have the strongest correlation with prognosis. These mutations could be future targets of therapy for chemoresistant patients, but more studies are required