The synergistic role of ATP-dependent drug efflux pump and focal adhesion signaling pathways in vinorelbine resistance in lung cancer.

Takao Nakanishi,Hiroshi Date,Makoto Sonobe,Masatsugu Hamaji,Hideki Motoyama,Toyofumi F Chen‐Yoshikawa,Kyoko Hijiya,Kei Shikuma,Koji Takahashi,Ryo Miyata,Akihiro Aoyama,Terumasa Sowa,Toshihiko Sato,Shigeto Nishikawa,Toshi Menju,Naoto Imamura

doi:10.1002/cam4.1282

Abstract

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 (ABCB1) was highly expressed in VR cells. A pathway analysis and western blot analysis revealed the high expression of integrins β1 and β3 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 ABCB1, had a synergistic effect with VRB in VR cells. In conclusion, ABCB1 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.

Highlights

Lung cancer remains the leading cause of cancer death in western countries [1]
Recent advances in advanced non–small cell lung cancer (NSCLC) therapy have focused on selective inhibitors that target driver mutations or genes that are critical to tumor growth and proliferation; this targeted therapy has led to dramatic clinical responses
We tested the effectiveness of cilengitide (CIL), an integrin αvβ3 inhibitor

Summary

Introduction

Recent advances in advanced non–small cell lung cancer (NSCLC) therapy have focused on selective inhibitors that target driver mutations or genes that are critical to tumor growth and proliferation; this targeted therapy has led to dramatic clinical responses [2, 3]. The conventional chemotherapeutic regimen continues to be used, as a postoperative adjuvant chemotherapy, because adjuvant epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) has shown no survival benefit [4]. As a postoperative adjuvant therapy, cisplatin plus vinorelbine (VRB) is the standard regimen because adjuvant cisplatin plus VRB shows a superior survival benefit in subgroup analyses [5]. 33–61% [6] without adjuvant therapy and 42–52% in a group that received adjuvant chemotherapy while lacking a residual tumor [7]. Adjuvant chemotherapy has a modest effect toward prolonging survival, with an absolute

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Results

Conclusion