Nebivolol Sensitizes BT-474 Breast Cancer Cells to FGFR Inhibitors

• Published in: Anticancer research Vol. 43; no. 5; pp. 1973 - 1980
• Main Authors: Kim, Yu Jin, Jang, Se-Kyeong, Kim, Gyeongmi, Hong, Sung-Eun, Park, Chan Sub, Seong, Min-Ki, Kim, Hyun-Ah, Kim, Kwang Seok, Kim, Chun-Ho, Park, Ki Soo, Hong, Jungil, Jin, Hyeon-Ok, Park, In-Chul
• Format: Journal Article
• Language: English
• Published: Greece International Institute of Anticancer Research 01.05.2023
• Subjects: AKT protein; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Cell Line, Tumor; Cell survival; Cell viability; Combined treatment; Down-regulation; Female; Fibroblast growth factor receptors; Gene expression; Growth factors; Humans; Inhibitors; Nebivolol - pharmacology; Nebivolol - therapeutic use; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins c-akt - metabolism; Receptors, Fibroblast Growth Factor - metabolism; Sensitivity enhancement; Signal Transduction; Signaling; siRNA; breast cancer; combination therapy; nebivolol; AKT; FGFR
• ISSN: 0250-7005; 1791-7530
• DOI: 10.21873/anticanres.16357

The fibroblast growth factor receptor (FGFR) signaling pathway is abnormally activated in human cancers, including breast cancer. Therefore, targeting the FGFR signaling pathway is a potent strategy to treat breast cancer. The purpose of this study was to find drugs that could increase sensitivity to FGFR inhibitor effects in BT-474 breast cancer cells, and to investigate the combined effects and underlying mechanisms of these combinations for BT-474 breast cancer cell survival. Cell viability was measured by MTT assay. Protein expression was determined by western blot analysis. mRNA expression was detected by Real-time PCR. Drug synergy effect was determined by isobologram analysis. Nebivolol, a third generation β1-blocker, synergistically increased the sensitivity of BT-474 breast cancer cells to the potent and selective FGFR inhibitors erdafitinib (JNJ-42756493) and AZD4547. A combination of nebivolol and erdafitinib markedly reduced AKT activation. Suppression of AKT activation using specific siRNA and a selective inhibitor further enhanced cell sensitivity to combined treatment with nebivolol and erdafitinib, whereas SC79, a potent activator of AKT, reduced cell sensitivity to nebivolol and erdafitinib. Enhanced sensitivity of BT-474 breast cancer cells to nebivolol and erdafitinib was probably associated with down-regulation of AKT activation. Combined treatment with nebivolol and erdafitinib is a promising strategy for breast cancer treatment.