BRAF INHIBITION DIMINISHES CELL VIABILITY VIA PKC ALPHA (PKCA) IN THYROID CANCER CELLS

CAMPOS HAEDO MN; DIAZ FLAQUÉ MC; DIAZ ALBUJA JA; PERONA M; DEBERNARDI MM; CAYROL MF; BARREIRO ARCOS ML; STERLE HA; JUVENAL GJ; CREMASCHI GA; ROSEMBLIT C

Congreso; Reunion Conjunta de Sociedades de Biociencias 2020; 2020

Thyroidcarcinoma (TC) is the most common endocrine neoplasia. Its incidence has increased in the last 40years worldwide. It comprisesa group of tumors of different lineage and biological behavior. About half of TC are driven by an acquired activatingmutation in the BRAF oncogene.While targeted therapies have improved outcomesin melanoma patients, most TC patients become resistant or recur suggesting that new or additivenon-cross-reactive therapies areneeded. We have previously shown that PKCa mediates TSH and thyroid hormones proliferative effectsin TC. Recent evidence indicatesthat together PKCa overexpression and BRAF mutation should contribute to tumorigenesis andresistance to anticancer therapies.We found that by inhibiting BRAF expression with RNAi in anaplastic TC cells with BRAF mutation,PKCa expression decreases aswell, suggesting that the latter is found downstream of BRAF. Furthermore, a decrease in the expressionof the cell proliferation markerPCNA was observed in BRAF-depleted cells by western blot analysis. Also, TC cells weresensitive to increasing doses of theBRAF inhibitor widely used in the clinic vemurafenib/PLX4032 in a dose-dependent manner (p<0.0001) byCell Titer Blue (CTB) assay.To begin to study the combined inhibition of PKC and BRAF, CTB assays were performed with increasingdoses of vemurafenib inpresence or absence of the PKC inhibitor GF109203X at selective concentrations in follicular TC cellscarrying BRAF mutation. We confirmedthe dose-dependency of vemurafenib and found that the combination leads to a significant decreasein cell viability (p<0.5). Ourresults establish that the effective dual PKCa and BRAF block-ade can significantly drive tumorproliferation inhibition. The results obtainedcould provide new therapeutic targets and alternatives to the treatments currently used for thisdisease. Despite its increasing incidenceand mortality in many cases, TC constitutes a very poorly studied area in our country.