title: Receptors for luteinizing hormone-releasing hormone (GnRH) as therapeutic targets in triple negative breast cancers (TNBC).
abstract: Triple negative breast cancers express receptors for gonadotropin-releasing hormone (GnRH) in more than 50% of the cases, which can be targeted with peptidic analogs of GnRH, such as triptorelin. The current study investigates cytotoxic activity of triptorelin as a monotherapy and in treatment combinations with chemotherapeutic agents and inhibitors of the PI3K and the ERK pathways in in vitro models of triple negative breast cancers (TNBC). GnRH receptor expression of TNBC cell lines MDA-MB-231 and HCC1806 was investigated. Cells were treated with triptorelin, chemotherapeutic agents (cisplatin, docetaxel, AEZS-112), PI3K/AKT inhibitors (perifosine, AEZS-129), an ERK inhibitor (AEZS-134), and dual PI3K/ERK inhibitor AEZS-136 applied as single agent therapies and in combinations. MDA-MB-231 and HCC1806 TNBC cells both expressed receptors for GnRH on messenger (m)RNA and protein level and were found sensitive to triptorelin with a respective median effective concentration (EC50) of 31.21 ± 0.21 and 58.50 ± 19.50. Synergistic effects occurred when triptorelin was combined with cisplatin. In HCC1806 cells, synergy occurred when triptorelin was applied with PI3K/AKT inhibitors perifosine and AEZS-129. In MDA-MB-231 cells, synergy was observed after co-treatment with triptorelin and ERK inhibitor AEZS-134 and dual PI3K/ERK inhibitor AEZS-136. GnRH receptors on TNBC cells can be used for targeted therapy of these cancers with GnRH agonist triptorelin. Treatment combinations based on triptorelin and PI3K and ERK inhibitors and chemotherapeutic agent cisplatin have synergistic effects in in vitro models of TNBC. If confirmed in vivo, clinical trials based on triptorelin and cisplatin could be quickly carried out, as triptorelin is FDA approved for other indications and known to be well tolerated.
authors.affiliation: Department of Gynecology and Obstetrics, University Medical Center Regensburg, 93053, Regensburg, Germany.
authors.forename: C W
authors.initials: CW
authors.lastname: Kwok
authors.forename: O
authors.initials: O
authors.lastname: Treeck
authors.forename: S
authors.initials: S
authors.lastname: Buchholz
authors.forename: S
authors.initials: S
authors.lastname: Seitz
authors.forename: O
authors.initials: O
authors.lastname: Ortmann
authors.forename: J B
authors.initials: JB
authors.lastname: Engel
mesh_terms: D000814:Aniline Compounds / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000737:chemistry; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002945:Cisplatin / Q000627:therapeutic use; D004252:DNA Mutational Analysis; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D007987:Gonadotropin-Releasing Hormone / Q000819:agonists* / Q000737:chemistry*; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010767:Phosphorylcholine / Q000031:analogs & derivatives / Q000627:therapeutic use; D011966:Receptors, LHRH / Q000378:metabolism; D064726:Triple Negative Breast Neoplasms / Q000378:metabolism*; D017329:Triptorelin Pamoate / Q000627:therapeutic use
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D011966:Receptors, LHRH; D017329:Triptorelin Pamoate; D010767:Phosphorylcholine; C105905:perifosine; D007987:Gonadotropin-Releasing Hormone; D019869:Phosphatidylinositol 3-Kinases; D002945:Cisplatin