ANALYSIS OF ANTI-HER2 DRUG INTERACTION IN HER2 POSITIVE HUMAN BREAST CANCER CELLS: SKBR3 AND BT-474

REDONDO, ANALÍA LOURDES; CASTRO, ANA CARLA; FLAMINI, MARINA INÉS; SANCHEZ, ANGEL MATIAS

San Luis

Congreso; XXXVII Reunión Científica Anual Sociedad de Biología de Cuyo; 2019

Breastcancer (BC) is the most common malignancy among women all over the world.Around 25% of all BC overexpress the human epidermal growth factor receptor 2(HER2) and it is traditionally associated with worse prognosis, shorteneddisease-free survival and overall survival. Trastuzumab (TZ) is the standardadjuvant treatment for this type of patients. It is well known that TZ hassurvival benefits when associated with chemotherapy in the treatment of patientwith early operable and metastatic HER2 positive BC. Although the TZ therapy hasbrought significant clinical benefits, not all patient respond. Moreover, thevast majorities of responders eventually relapse and suffer heart diseases too.So the TZ resistance and cardiotoxicity are clinical important problems. Thus,it is necessary to develop new therapeutic approaches based on the combinationof different existing and FDA?s approved drugs. In this study we evaluated theeffect of different concentrations (0.1-1-10 ug/ml) of anti-HER2 therapies suchas TZ, Trastuzumab-emtansine (TD) and Lapatinib (LP), alone and in combination,to determinate their effect on the cell proliferation and to evaluatesynergistic effects between drugs in two breast cancer cell lines: SKBR3 andBT-474. To study drug interactions, we performed MTT assays and to evaluatedsynergism and antagonism between drugs we used Computer Software ProgramCompuSyn. Our results indicate that 72 hours treatments with different doses ofTZ, TD, LP and their combinations are effective decreasing SKBR3 and BT-474 cellsproliferation and LP has the greatest effect decreasing it. The SKBR3 cells aremore sensitive to treatments than BT-474 cells. The analysis of pharmacologicalinteraction in SKBR3 cells showed synergism in the combination TZ+LP (10:1µg/ml) and TZ+LP (10:10 µg/ml), and in these concentration is possible a 10fold TZ reduction achieving the same therapeutic effect. Additionally TD+LPexhibited synergism in all doses tested and in TD+LP (10:1 µg/ml) and TD+LP(10:10 µg/ml) is possible a 10 fold TD reduction achieving the same therapeuticeffect. On the other hand, in BT-474 cells we observed synergism between TD+LPin all doses tested and only in the lowest dose for TZ+LP (1:0.1 µg/ml). Afavorable 10 fold TZ or TD dose reduction is possible for combination 10:1µg/ml and 10:100 µg/ml in TZ+LP and TD+LP. In conclusion, the coadministrationof anti-HER2 therapies with different mechanism action in patients with HER2+BC could contribute to improve their prognosis and reduce the adverse effectsof therapy because the TZ or TD doses applied would be lower due to theadjuvant effect of LP.