Fingolimod sensitizes EGFR wildtype nonsmall cell lung cancer cells to lapatinib or sorafenib and induces cell cycle arrest.
Oncol Rep
; 42(1): 231-242, 2019 Jul.
Article
em En
| MEDLINE
| ID: mdl-31059070
ABSTRACT
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 firstline therapies for patients with advanced nonsmall cell lung cancer (NSCLC) with activating EGFR mutations, but are not effective in patients with wildtype EGFR. In the present study, the cytotoxic effects of various TKIs against EGFR were investigated in wildtype 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 transcriptionquantitative 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 wildtype EGFR, by sensitizing NSCLC cells to TKIs.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Ciclo Celular
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Carcinoma Pulmonar de Células não Pequenas
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Resistencia a Medicamentos Antineoplásicos
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Inibidores de Proteínas Quinases
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Cloridrato de Fingolimode
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Neoplasias Pulmonares
Limite:
Humans
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article