COMBINATION TREATMENT OF RETINOIC ACID PLUS FAK INHIBITOR PREVENTS TUMOR GROWTH AND BREAST CANCER CELLS METASTASIS

CASTRO GUIJARRO, AC; VANDERHOEVEN, F; MONDACA, JM; FERNANDEZ-MUÑOZ, JM; REDONDO, A; SANCHEZ, AM; FLAMINI, MI

Workshop; 2nd International Workshop on Translational Cancer Research; 2021

Background and Aims:All-trans retinoic acid (RA) and its natural and synthetic derivatives, known as retinoids, are promisingagents in the treatment and chemoprevention of different neoplasias including breast cancer (BC). Focaladhesion kinase (FAK) is a key regulator of cell motility and its overexpression has been associated to ametastatic behavior of tumors. Thus, pharmaceutical FAK inhibitors (FAKi) have been developed tocounter this action. In this work, we evaluated the effect of RA+FAKi combination in tumor progression.Methods:The murine mammary adenocarcinoma cell line LM3 was used. MTT, pharmacological interaction analysis,western blot, immunofluorescence, adhesion, and migration assays were performed. The orthotopictumor growth and lung metastasis assay were achieved. To bioinformatics analysis we used the publiclyGene Expression Omnibus database.Results:Bioinformatic data show that the expression of RARA, SRC, PTK2 (FAK) is high, meanwhile RARB and RARGare underexpressed in BC cells. We reveal that in metastatic BC cells, genes encoding proteins that aredirectly or indirectly modulated by FAK, are deregulated in comparison with normal cells. We showed adifferent pattern of genes up/down-regulated between RA-resistant and RA-sensitive BC cells.Additionally, we demonstrated that although RA and FAKi administered separately decrease cell viability,adhesion and migration in LM3 cells, their combination exerts a higher effect. In an orthotopic assay ofLM3 tumor growth, RA and FAKi separately reduce tumor growth however the combined treatmentinduced the stronger inhibition. Furthermore, the combination increase mice survival. In an experimentalmetastatic assay, RA significantly reduced lung metastatic dissemination.Conclusions:These results suggested that RA resistance would reflect a deregulation of most of the RA-target genesinvolved in cell adhesion, migration and invasion. RA+FAKi improves reducing tumor growth andmetastasis increasing mice survival. This suggest that the sensibility to RA therapy could be exacerbatedwith FAKi coadministration in BC tumors.