PARP Inhibitors in Endometrial Cancer: Current Status and Perspectives

Abstract

Advanced, recurrent and metastatic endometrial cancer (EC) has a dismal prognosis due to poor response rates to conventional treatments. In the era of precision medicine, the improved understanding of cancer genetics and molecular biology has led to the development of targeted therapies, such as poly (ADP-ribose) polymerase (PARP) inhibitors. This class of drugs that inhibit PARP enzymes has been investigated in many different types of tumors and its use in the treatment of gynecological malignancies has rapidly increased over the past few years. Data from several clinical trials showed that PARP inhibitors have a beneficial role in cancers with a defect in the homologous DNA recombination system, regardless of the BRCA mutational status. Since EC frequently shows mutations in PTEN and TP53 genes, indirectly involved in the homologous DNA recombination pathway, several in vivo and in vitro studies investigated the efficacy of PARP inhibitors in EC, showing promising results. This review will discuss the use of PARP inhibitors in endometrial cancer, summarizing data from preclinical studies and providing an overview of the ongoing trials, with a special focus on the development of combined treatment strategies with PARP inhibitors and immune checkpoint inhibitors.

Keywords: P53 mutation; PARP inhibitors; PTEN mutation; endometrial cancer; homologous recombination deficiency; immune checkpoint inhibitors.

Figure 1

Overview of the HR pathway in PTEN-deficient EC cells. When DSBs occur, ATM, ATR and CHK1/2 kinases phosphorylate BRCA1, that is stabilized by BARD1. BRCA2, whose correct conformation is maintained by DSS1 and PALB2, carries RAD51 to the site of DNA damage, where it forms nucleoprotein filaments and stabilizes DNA double strands. The EGFR activates PI3K/AKT pathway, that in turn inhibits p53. Conversely, PTEN inhibits the PI3K pathway and thus activates p53, that induces cell apoptosis and cycle arrest and increases the expression of the RAD51 and the MRN complex (RAD50, MRE11, NBS1), involved in the DSBs repair. Moreover, PTEN upregulates RAD51. Therefore, mutant PTEN inhibits p53 and RAD51 expression, thus impairing the HR system. Similarly, mutant p53 downregulates the MRN complex and RAD51 levels.