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

Kohki Ota, Takashi Okuma, Alberto De Lorenzo, Ayuka Yokota, Hirotsugu Hino, Hiromi Kazama, Shota Moriya, Naoharu Takano, Masaki Hiramoto, Keisuke Miyazawa

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)231-242
Number of pages12
JournalOncology Reports
Issue number1
Publication statusPublished - Jul 2019
Externally publishedYes


  • Cell cycle arrest
  • Endoplasmic recticulum stress loading
  • Epidermal growth factor receptor
  • Fingolimod
  • Non-small cell lung cancer
  • Tyrosine kinase inhibitors


Dive into the research topics of 'Fingolimod sensitizes EGFR wild-type non-small cell lung cancer cells to lapatinib or sorafenib and induces cell cycle arrest'. Together they form a unique fingerprint.

Cite this