Background: Breast cancer is the most common cancer overall, with an estimated 2.4 million incident cases in 2015. Current treatment of breast cancer is mainly surgery, chemotherapy, radiotherapy, and hormonal therapy. Although these approaches appear to be effective, they have failed to result in long-term cure, especially for aggressive HER2-positive and triple-negative breast cancer. This particularly holds for sub-Saharan Africa with a dominance of aggressive breast cancer subtypes with very limited treatment options and almost no research activities in place. As a result, continuous exploration of alternative treatment strategies is urgently required. Consequently, a collaborative research program has been established between Addis Ababa University, Ethiopia, and Martin-Luther-University, Germany, to enhance breast cancer research in Ethiopia. As a pilot study in Germany, we have assessed the in vitro potency of the three inhibitors romidepsin, trametinib, and lapatinib targeting HDAC, MEK and HER2/EGFR, respectively, in different breast cancer cell lines.
Methods: Seven distinct breast cancer cell lines (MCF7, SKBR3, T47D, BT474, BT20, HCC1806 and HCC1937) of known HER-2 and hormone status were used to evaluate the antiproliferative effect of romidepsin, lapatinib, and trametinib. Cells cultivated in complete RPMI media were seeded in to 96 well plates (3,000 cells/well) and incubated at 370C and 5% CO2 for 24hrs. The cells were then treated for 24, 48, and 72 hours with different concentrations of the drugs. Cells exposed to solvent alone served as controls. XTT cell viability assay was used to determine proliferation of cells following manufacturers' instruction. IC50 value was calculated (Compusyn software) for each drug against the different cell lines to determine the antiproliferative effect.
Results: Romidepsin exhibited a strong antiproliferative effect against all breast cancer cell lines tested, resulting in a marked decrease in cell viability with increasing concentrations, which highly varied between the breast cancer cell lines analyzed. The calculated IC50 values 48 hrs after the onset of treatment ranged between 2.2 and 52 nM; T47D was the most sensitive. Lapatinib treatment of the EGFR/HER-2 expressing BT20, SKBR3 and BT474 caused dose-dependent suppression of cell viability against SKBR3 and BT474 with an IC50 value of 450 and 77 nM, respectively. In contrast, BT20 cells were resistant to this treatment and were the only breast cancer cell line with an enhanced sensitivity to increasing concentrations of trametinib (IC50 =2.79 μM).
Conclusion: In sum, romidepsin might improve the treatment efficacy of breast cancer though it needs to be further explored in vitro as well as in vivo alone and in combination with other therapies. Although trametinib has been suggested to be insufficient for monotherapy of breast cancer in general, it might be still a candidate for the treatment of basal-like breast cancers due to the sensitivity of BT20 cells.
Citation Format: Meron Yohannes Nigussie, Jürgen Bukur, Zelalem Desalegn Woldesonbet, Tamrat Abebe Zeleke, Yonas Bekuretsion, Mahlet Arayselassie, Mathewos Assefa, Abebe Bekele, Endale Anberber, Martina Vetter, Claudia Wickenhauser, Eva J Kantelhardt, Barbara Seliger. Antiproliferative efficacy of different targeted drugs on breast cancer cell lines of distinct subtypes [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr B020.