Fingolimod sensitizes EGFR wild‑type non‑small cell lung cancer cells to lapatinib or sorafenib and induces cell cycle arrest

• Published in: Oncology reports Vol. 42; no. 1; pp. 231 - 242
• Main Authors: Ota, Kohki, Okuma, Takashi, Lorenzo, Alberto, Yokota, Ayuka, Hino, Hirotsugu, Kazama, Hiromi, Moriya, Shota, Takano, Naoharu, Hiramoto, Masaki, Miyazawa, Keisuke
• Format: Journal Article
• Language: English
• Published: Greece Spandidos Publications 01.07.2019; Spandidos Publications UK Ltd
• Subjects: A549 Cells; Antibiotics; Apoptosis; Autophagy; Autophagy-Related Proteins - metabolism; Biotechnology industries; Breast cancer; Cancer cells; Cancer therapies; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - metabolism; Cell cycle; Cell Cycle - drug effects; Cell growth; Cell Line, Tumor; Cell Movement - drug effects; Cell Proliferation - drug effects; Cell Survival - drug effects; Cytotoxicity; Drug Repositioning; Drug Resistance, Neoplasm - drug effects; Drug Synergism; Drugs; Epidermal growth factor; Epidermal growth factors; ErbB Receptors - genetics; Fingolimod; Fingolimod Hydrochloride - pharmacology; Genes; Genetic aspects; Humans; Inhibitor drugs; Kinases; Lapatinib; Lapatinib - pharmacology; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Multiple sclerosis; Mutation; Non-small cell lung cancer; Phenols (Class of compounds); Phosphorylation; Polymerase chain reaction; Protein Kinase Inhibitors - pharmacology; Proteins; Scientific equipment industry; Small cell lung cancer; Sorafenib; Sorafenib - pharmacology; Targeted cancer therapy; Tumors; Tyrosine; United States; Japan; United States > US
• DOI: 10.3892/or.2019.7140
• ISSN: 1021-335X; 1791-2431

Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase and mutations in this gene are major drivers of lung cancer development. EGFR tyrosine kinase inhibitors (TKIs) are standard first‑line therapies for patients with advanced non‑small cell lung cancer (NSCLC) with activating EGFR mutations, but are not effective in patients with wild‑type EGFR. In the present study, the cytotoxic effects of various TKIs against EGFR were investigated in wild‑type NSCLC cells as single treatments or in combination with Fingolimod (FTY720), which has been approved for treating multiple sclerosis and has cytotoxic effects against several tumor cell lines. It was found that the combined treatment with TKIs lapatinib (Lap) or sorafenib (Sor) and FTY720 synergistically suppressed the viability of the NSCLC cell lines A549 and H596. Additionally, FTY720 inhibited lysosomal acidification and suppressed autophagy flux. Immunoblotting and reverse transcription‑quantitative polymerase chain reaction showed that FTY720 combined with Lap or Sor, enhanced endoplasmic reticulum (ER) stress loading and cell cycle arrest in A549 cells. The enhancement of ER stress loading and cell cycle arrest induced by combined treatment with Lap or Sor and FTY720, which was associated with the cytotoxicity induced by the combination of these drugs. These findings suggested that FTY720 improved TKI therapy in NSCLC patients with wild‑type EGFR, by sensitizing NSCLC cells to TKIs.