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.