Open AccessThe synergistic role of ATP ‐dependent drug efflux pump and focal adhesion signaling pathways in vinorelbine resistance in lung cancer
Author(s) -
Nakanishi Takao,
Menju Toshi,
Nishikawa Shigeto,
Takahashi Koji,
Miyata Ryo,
Shikuma Kei,
Sowa Terumasa,
Imamura Naoto,
Hamaji Masatsugu,
Motoyama Hideki,
Hijiya Kyoko,
Aoyama Akihiro,
Sato Toshihiko,
ChenYoshikawa Toyofumi F.,
Sonobe Makoto,
Date Hiroshi
Publication year - 2018
Publication title -
cancer medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 53
ISSN - 2045-7634
DOI - 10.1002/cam4.1282
Subject(s) - cancer research , focal adhesion , a549 cell , protein kinase b , signal transduction , lung cancer , fyn , vinorelbine , pi3k/akt/mtor pathway , src family kinase , proto oncogene tyrosine protein kinase src , biology , microbiology and biotechnology , medicine , cisplatin , pathology , chemotherapy
The vinorelbine ( VRB ) plus cisplatin regimen is widely used to treat non–small cell lung cancer ( NSCLC ), but its cure rate is poor. Drug resistance is the primary driver of chemotherapeutic failure, and the causes of resistance remain unclear. By focusing on the focal adhesion ( FA ) pathway, we have highlighted a signaling pathway that promotes VRB resistance in lung cancer cells. First, we established VRB ‐resistant ( VR ) lung cancer cells ( NCI ‐H1299 and A549) and examined its transcriptional changes, protein expressions, and activations. We treated VR cells by Src Family Kinase ( SFK ) inhibitors or gene silencing and examined cell viabilities. ATP ‐binding Cassette Sub‐family B Member 1 ( ABCB 1 ) was highly expressed in VR cells. A pathway analysis and western blot analysis revealed the high expression of integrins β 1 and β 3 and the activation of FA pathway components, including Src family kinase ( SFK ) and AKT , in VR cells. SFK involvement in VRB resistance was confirmed by the recovery of VRB sensitivity in FYN knockdown A549 VR cells. Saracatinib, a dual inhibitor of SFK and ABCB 1, had a synergistic effect with VRB in VR cells. In conclusion, ABCB 1 is the primary cause of VRB resistance. Additionally, the FA pathway, particularly integrin, and SFK , are promising targets for VRB ‐resistant lung cancer. Further studies are needed to identify clinically applicable target drugs and biomarkers that will improve disease prognoses and predict therapeutic efficacies.