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

CASTRO GUIJARRO, ANA CARLA; REDONDO ANALIA LOURDES; SANCHEZ ANGEL MATIAS; FLAMINI MARINA INES

San Luis

Congreso; XXXVII REUNION CIENTIFICA ANUAL DE LA SOCIEDAD DE BIOLOGIA DE CUYO; 2019

SOCIEDAD DE BIOLOGIA DE CUYO

Breast cancer (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, shortened disease-free survival and overall survival. Trastuzumab (TZ) is the standard adjuvant treatment for this type of patients. It is well known that TZ has survival benefits when associated with chemotherapy in the treatment of patient with early operable and metastatic HER2 positive BC. Although the TZ therapy has brought significant clinical benefits, not all patient respond. Moreover, the vast 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 combination of different existing and FDA?s approved drugs. In this study we evaluated the effect of different concentrations (0.1-1-10 ug/ml) of anti-HER2 therapies such as TZ, Trastuzumab-emtansine (TD) and Lapatinib (LP), alone and in combination, to determinate their effect on the cell proliferation and to evaluate synergistic effects between drugs in two breast cancer cell lines: SKBR3 and BT-474. To study drug interactions, we performed MTT assays and to evaluated synergism and antagonism between drugs we used Computer Software Program CompuSyn. Our results indicate that 72 hours treatments with different doses of TZ, TD, LP and their combinations are effective decreasing SKBR3 and BT-474 cells proliferation and LP has the greatest effect decreasing it. The SKBR3 cells are more sensitive to treatments than BT-474 cells. The analysis of pharmacological interaction in SKBR3 cells showed synergism in the combination TZ+LP (10:1 µg/ml) and TZ+LP (10:10 µg/ml), and in these concentration is possible a 10 fold TZ reduction achieving the same therapeutic effect. Additionally TD+LP exhibited 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 therapeutic effect. On the other hand, in BT-474 cells we observed synergism between TD+LP in all doses tested and only in the lowest dose for TZ+LP (1:0.1 µg/ml). A favorable 10 fold TZ or TD dose reduction is possible for combination 10:1 µg/ml and 10:100 µg/ml in TZ+LP and TD+LP. In conclusion, the coadministration of anti-HER2 therapies with different mechanism action in patients with HER2+ BC could contribute to improve their prognosis and reduce the adverse effects of therapy because the TZ or TD doses applied would be lower due to the adjuvant effect of LP.