Lupeol synergizes with 5-fluorouracil to combat c-MET/EphA2 mediated chemoresistance in triple negative breast cancer
Debarpan Mitra, Depanwita Saha, Gaurav Das, Rimi Mukherjee, Samir Banerjee, Neyaz Alam, Saunak Mitra Mustafi, Partha Nath, Anuj Majumder, Biswanath Majumder, Nabendu Murmu
Abstract
Triple-negative breast cancer (TNBC) is the most elusive subtype of breast cancer that encounters treatment dilemmas owing to the paucity of druggable targets. We found hyperactivation of c-MET and ephrin type-A receptor 2 (EphA2) in patients treated with 5FU driven chemotherapy which correlated with lower disease-free survival. However, silencing of both these genes resulted in a marked decrease in the invasive, migratory, and tumorigenic potential of TNBC cells, indicating that a dual target strategy is actionable. Lupeol is a phytochemical, with potent anticancer efficacy and minimal side effects in preclinical studies. A synergistic strategy with 5FU and Lupeol elicited promising anticancer responses in vitro , in vivo , and in patient-derived ex vivo tumor culture models. This synergistic regimen is effective, even in the presence of HGF, which mechanistically orchestrates the activation of c-MET and EphA2. These data lay the foundation for the clinical validation of this combination therapy for TNBC patients.