Nicole M. Nieves Aviles
Gabriel O Rodríguez-Vázquez
Iris K Salgado-Villanueva
Walter I Silva Ortiz
Héctor M Maldonado
Pharmacology Department, Universidad Central del Caribe, Bayamón, Puerto Rico
Physiology Department, Medical Sciences Campus, University of Puerto Rico, San Juan, Puerto Rico
Introduction
Breast cancer, particularly triple-negative breast cancer (TNBC), poses significant treatment challenges due to its aggressive nature and resistance to conventional therapies. This study hypothesizes that inhibiting WEE1 can help overcome chemotherapy resistance in TNBC by enhancing the effectiveness of existing treatments through drug synergy.
Methods
We examined the pharmacodynamic synergy between DNA-damaging agents (doxorubicin, cisplatin, and 5-fluorouracil [5-FU]) and the WEE1 inhibitor adavosertib in breast cancer cell lines, MDA-MB-231 (TNBC) and non-transformed MCF10-A cells. Drug interactions were assessed through concentration-inhibition proliferation assays (Alamar Blue) and synergy software.
Results
In MDA-MB-231 cells, IC50 values were 0.8105 µM (doxorubicin), 15.36 µM (cisplatin), 87.39 µM (5-FU), and 0.3907 µM (adavosertib). In MCF10-A cells, doxorubicin’s IC50 was lower, while adavosertib’s was higher at 4.853 µM. The doxorubicin-adavosertib combination displayed moderate synergy in MCF10-A cells (synergy score of 8.29%) and weak synergy in MDA-MB-231 cells (4.24%). The cisplatin-adavosertib combination showed weak synergy in MDA-MB-231 (2.34%) but antagonism in MCF10-A (-4.09%). Similarly, the 5-FU-adavosertib combination displayed weak synergy in MDA-MB-231 (0.24%) and antagonism in MCF10-A (-1.76%). Combination sensitivity scores (CSS) favored the doxorubicin-adavosertib combination in both cell lines.
Conclusions
The findings underscore the potential of combining WEE1 inhibition with DNA-damaging agents to improve chemotherapy efficacy, highlighting the importance of evaluating drug interactions in different cell types to optimize treatment strategies.
Keywords
TNBC; Breast Cancer; DNA-dt; Synergy; WEE1
