title: Chemoresistance and targeted therapies in ovarian and endometrial cancers.
abstract: Gynecological cancers are known for being very aggressive at their advanced stages. Indeed, the survival rate of both ovarian and endometrial cancers is very low when diagnosed lately and the success rate of current chemotherapy regimens is not very efficient. One of the main reasons for this low success rate is the acquired chemoresistance of these cancers during their progression. The mechanisms responsible for this acquired chemoresistance are numerous, including efflux pumps, repair mechanisms, survival pathways (PI3K/AKT, MAPK, EGFR, mTOR, estrogen signaling) and tumor suppressors (P53 and Par-4). To overcome these resistances, a new type of therapy has emerged named targeted therapy. The principle of targeted therapy is simple, taking advantage of changes acquired in malignant cancer cells (receptors, proteins, mechanisms) by using compounds specifically targeting these, thus limiting their action on healthy cells. Targeted therapies are emerging and many clinical trials targeting these pathways, frequently involved in chemoresistance, have been tested on gynecological cancers. Despite some targets being less efficient than expected as mono-therapies, the combination of compounds seems to be the promising avenue. For instance, we demonstrate using ChIP-seq analysis that estrogen downregulate tumor suppressor Par-4 in hormone-dependent cells by directly binding to its DNA regulatory elements and inhibiting estrogen signaling could reinstate Par-4 apoptosis-inducing abilities. This review will focus on the chemoresistance mechanisms and the clinical trials of targeted therapies associated with these, specifically for endometrial and ovarian cancers.
authors.affiliation: Research Group in Cellular Signaling, Department of Medical Biology, Université du Québec à Trois-Rivières, Trois-Rivières, Québec, Canada.
authors.forename: Kevin
authors.initials: K
authors.lastname: Brasseur
authors.affiliation: Département de Biologie, Faculté des Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Gévry
authors.affiliation: Research Group in Cellular Signaling, Department of Medical Biology, Université du Québec à Trois-Rivières, Trois-Rivières, Québec, Canada.
authors.forename: Eric
authors.initials: E
authors.lastname: Asselin
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D002986:Clinical Trials as Topic; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000235:genetics; D004967:Estrogens / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D053263:Gene Regulatory Networks / Q000187:drug effects; D006801:Humans; D058990:Molecular Targeted Therapy / Q000379:methods*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics; D016896:Treatment Outcome
chemical_list: D051017:Apoptosis Regulatory Proteins; D004967:Estrogens; C101296:prostate apoptosis response-4 protein
keywords: PI3K; chemoresistance; estrogen; gynecological cancers; targeted therapies