SYNERGISTIC ANTITUMOR ACTIVITY BY COMBINING RETINOIC ACID WITH FOCAL ADHESION KINASE INHIBITOR

MONDACA JM; SÁNCHEZ AM ; CASTRO GUIJARRO AC; VARGAS ROIG LM.; REDONDO AL; FLAMINI MI

Congreso; XXXVII REUNIÓN CIENTIFICA ANUAL DE LA SOCIEDAD DE BIOLOGÍA DE CUYO; 2019

Breast cancer (BC) is a common malignant disease worldwide. Retinoids are currently being used in clinical trials to treat or prevent cancer progression and have been proposed as an adjuvant treatment of breast carcinoma because of its ability to inhibit cell growth. We have previously demonstrated that long retinoic acid (RA) treatment (10-6M) reduced cellular adhesion and migration in BC cells. In addition, we verified that the administration of trastuzumab (TZ) in combination with RA synergistically decreased cell survival, adhesion/migration/invasion in BC cells. TZ+RA strongly reduced Focal Adhesion Kinase (FAK) expression and induced nuclear FAK translocation. We speculate that RA+FAK inhibitor (FAKi) could reduce tumor growth and tumor formation by preventing tumor adhesion. We used LM3 cell line, derived from a murine mammary adenocarcinoma, with tumorigenic and metastatic capacity in BALB/c mice treated or not with FAKi for 72 h. We performed an orthotopic assay evaluating LM3 tumor growth in the mammary gland of female BALB/c bearing or not a slow-release RA (10 mg) -containing subcutaneous silastic pellet or an empty pellet as control. RA and FAKi separately reduce the tumor growth but the combined treatment induced a stronger inhibition in tumor volume. In addition, each drug seems to increase mice survival but only the combination of drugs is statistically significant. Furthermore, we also performed an experimental metastatic assay. Then LM3 cells pretreated or not with FAKi for 72 h were injected into the tail vein of mice bearing or not RA -containing pellet. RA significantly reduced lung metastatic dissemination. FAKi and the combination RA+FAKi presented a lower, but nonsignificant, number of lung nodules than the control group. In conclusion, the sensibility to RA therapies could be increased with FAKi coadministration in BC tumors.