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
Affiliations
Debarpan Mitra
Department of Signal Transduction and Biogenic Amines, Chittaranjan National Cancer Institute, 37, S. P. Mukherjee Road, Kolkata 700026, India
Depanwita Saha
Department of Signal Transduction and Biogenic Amines, Chittaranjan National Cancer Institute, 37, S. P. Mukherjee Road, Kolkata 700026, India
Gaurav Das
Department of Signal Transduction and Biogenic Amines, Chittaranjan National Cancer Institute, 37, S. P. Mukherjee Road, Kolkata 700026, India
Rimi Mukherjee
Department of Signal Transduction and Biogenic Amines, Chittaranjan National Cancer Institute, 37, S. P. Mukherjee Road, Kolkata 700026, India
Samir Banerjee
Department of Signal Transduction and Biogenic Amines, Chittaranjan National Cancer Institute, 37, S. P. Mukherjee Road, Kolkata 700026, India
Neyaz Alam
Department of Surgical Oncology, Chittaranjan National Cancer Institute, 37, S. P. Mukherjee Road, Kolkata 700026, India
Saunak Mitra Mustafi
Department of Pathology, Chittaranjan National Cancer Institute, 37, S. P. Mukherjee Road, Kolkata 700026, India
Partha Nath
Department of Surgical Oncology, Chittaranjan National Cancer Institute, 37, S. P. Mukherjee Road, Kolkata 700026, India
Anuj Majumder
Department of Medicine, Harvard Medical School, 65 Lansdowne Street, Suite #317, Cambridge, MA 02139, USA; Brookline High School, 115 Greenough Street, Brookline, MA 02445, USA
Biswanath Majumder
Departments of Molecular Profiling, Cancer Biology and Molecular Pathology, Mitra Biotech, Bangalore, India
Nabendu Murmu
Department of Signal Transduction and Biogenic Amines, Chittaranjan National Cancer Institute, 37, S. P. Mukherjee Road, Kolkata 700026, India; Corresponding author
Summary: 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.
