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

doi:10.1016/j.isci.2023.108395

Lupeol synergizes with 5-fluorouracil to combat c-MET/EphA2 mediated chemoresistance in triple negative breast cancer

iScience. 2023 Nov 4;26(12):108395. doi: 10.1016/j.isci.2023.108395. eCollection 2023 Dec 15.

Authors

Affiliations

¹ Department of Signal Transduction and Biogenic Amines, Chittaranjan National Cancer Institute, 37, S. P. Mukherjee Road, Kolkata 700026, India.
² Department of Surgical Oncology, Chittaranjan National Cancer Institute, 37, S. P. Mukherjee Road, Kolkata 700026, India.
³ Department of Pathology, Chittaranjan National Cancer Institute, 37, S. P. Mukherjee Road, Kolkata 700026, India.
⁴ Department of Medicine, Harvard Medical School, 65 Lansdowne Street, Suite #317, Cambridge, MA 02139, USA.
⁵ Brookline High School, 115 Greenough Street, Brookline, MA 02445, USA.
⁶ Departments of Molecular Profiling, Cancer Biology and Molecular Pathology, Mitra Biotech, Bangalore, India.

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.

Keywords: Cancer; Cell biology; Phytopharmacy.