Therapeutic potential of GNRHR analogs and SRC/FAK inhibitors to counteract tumor growth and metastasis in breast cancer

Abstract

Breast cancer (BC) is the leading cause of cancer death in women, with hormone-dependent BC accounting for about 80 % of cases, primarily affecting postmenopausal women with gonadotropins, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) elevated. Treatments targeting the gonadotropin-releasing hormone receptor (GnRHR), such as the agonist leuprorelin (LEU) and antagonist degarelix (DEGA), are used for hormone-dependent tumors. While the functional role of gonadotropin receptors in extragonadal tissues remains uncertain, recent studies suggest LH contributes to tumor development and progression. Tumor progression involves reorganization in the actin cytoskeleton, induction of adhesion, and cell migration, driven by proteins such as Src and the focal adhesion kinase (FAK), which are related to invasive behaviors. The overexpression of both protein kinases generates an invasive and metastatic phenotype, then inhibitors targeting Src (PP2) and FAK (FAKi) have been developed to counteract this effect. This study combined GnRH analogs with Src and FAK inhibitors to target BC progression. We found that LH treatment influenced gene expression linked to tumor development. Examining the GnRHR-LEU and GnRHR-DEGA complexes revealed structural differences affecting ligand binding. In an orthotopic tumor model, DEGA reduced tumor growth, while LEU had the opposite effect. Combining DEGA with PP2 or FAKi enhanced tumor inhibition, improving mice survival. These findings provide valuable insights into the essential regulatory role of gonadotropins in genes involved in tumorigenic processes, highlighting the potential of GnRHR antagonists combined with Src or FAK inhibitors as a promising strategy to develop new drugs that interfere with the ability of breast tumor progression.