Afatinib reverses ceritinib resistance (CR) in ALK/ROS1-positive non-small-cell lung cancer cell (NSCLC) via suppression of NRG1 pathway
Authors Chen H, Zhang Q, Zhang Y, Jia B, Zhang B, Wang C
Received 3 May 2018
Accepted for publication 25 June 2018
Published 26 November 2018 Volume 2018:11 Pages 8201—8209
Checked for plagiarism Yes
Review by Single-blind
Peer reviewer comments 2
Editor who approved publication: Dr William Cho
Hui Chen,1–4 Qiang Zhang,1–4 Yu Zhang,1–4 Bin Jia,1–4 Bin Zhang,1–4 Changli Wang1–4
1Department of Lung Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, People’s Republic of China; 2Key Laboratory of Cancer Prevention and Therapy, Tianjin, People’s Republic of China; 3Tianjin’s Clinical Research Center for Cancer, Tianjin, People’s Republic of China; 4Tianjin Lung Cancer Center, Tianjin, People’s Republic of China
Background: Lung cancer (LC) is the most prevalent malignancy worldwide, and non-small-cell LC (NSCLC) cell is associated with high mortality. As a member of the second generation of anaplastic lymphoma kinase (ALK) suppressors, ceritinib has considerable therapeutic effects for ALK and c-ros oncogene 1 (ROS1)-positive NSCLC cell. Nevertheless, patients inevitably develop resistance to the drug. Our research focused on the exploration of whether afatinib was able to counteract ceritinib resistance (CR) in NSCLC cells with positive ALK or ROS1.
Materials and methods: Acquired CR cell sublines (HCC78R and H1299R) were induced by stepwise escalation of ceritinib exposure. MTT assay was used to validate cell proliferation. Fluorescence assay was performed for apoptosis analysis. Quantitative real-time PCR and Western blot assays were used to assess the alterations of signaling pathway-related mRNA and proteins, respectively.
Results: We found that prolonged treatment of HCC78 and H1299 with ceritinib brought about 10 times weaker ceritinib sensitivity (CS) in comparison with parent cells. Additionally, the results showed that afatinib efficiently promoted CS, which was evidenced as reduced proliferation and cell death promotion, in NSCLC cells, irrespective of their previous sensitivity or resistance to ceritinib. Moreover, afatinib decreased neuregulin-1 (NRG1) signaling stimulation in CR as well as CS cells. Furthermore, supplementing NRG1 in H1299 and HCC78 cells triggered CR, which was attenuated by afatinib.
Conclusion: These results demonstrated that afatinib overcame CR in NSCLC cells with positive ALK or ROS1 by inhibiting the NRG1 signaling pathway, which might be a promising therapeutic approach.
Keywords: afatinib, ceritinib, NRG1, lung cancer, ALK/ROS1
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