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Title: | Combination therapy of gefitinib and miR-30a-5p may overcome acquired drug resistance through regulating the PI3K/AKT pathway in non-small cell lung cancer | Authors: | Wang, F Meng, F Wong, SCC Cho, WCS Yang, S Chan, LWC |
Issue Date: | 2020 | Source: | Therapeutic advances in respiratory disease, 2020, v. 14 | Abstract: | Background: Non-small cell lung cancer (NSCLC) patients with an epidermal growth factor receptor (EGFR) mutation often initially respond to EGFR tyrosine kinase inhibitor (EGFR-TKI) treatment but may acquire drug resistance due to multiple factors. MicroRNAs are a class of small noncoding and endogenous RNA molecules that may play a role in overcoming the resistance. Materials and methods: In this study, we explored and validated, through in vitro experiments and in vivo models, the ability of a combination treatment of EGFR-TKI, namely gefitinib, and a microRNA mimic, miR-30a-5p, to overcome drug resistance through regulation of the insulin-like growth factor receptor-1 (IGF1R) and hepatocyte growth factor receptor signaling pathways, which all converge on phosphatidylinositol 3 kinase (PI3K), in NSCLC. First, we examined the hypothesized mechanisms of drug resistance in H1650, H1650-acquired gefitinib-resistance (H1650GR), H1975, and H460 cell lines. Next, we investigated a potential combination treatment approach to overcome acquired drug resistance in the H1650GR cell line and an H1650GR cell implanted mouse model. Results: Dual inhibitors of EGFR and IGF1R significantly lowered the expression levels of phosphorylated protein kinase B (p-AKT) and phosphorylated mitogen-activated protein kinase (p-ERK) compared with the control group in all cell lines. With the ability to repress PI3K expression, miR-30a-5p mimics induced cell apoptosis, and inhibited cell invasion and migration in the treated H1650GR cell line. Conclusion: Gefitinib, combined with miR-30a-5p mimics, effectively suppressed the growth of H1650GR-induced tumor in xenografts. Hence, a combination therapy of gefitinib and miR-30a-5p may play a critical role in overcoming acquired resistance to EGFR-TKIs. The reviews of this paper are available via the supplemental material section. |
Keywords: | Combination therapy Drug resistance Epidermal growth factor receptor Gefitinib miR-30a-5p Non-small cell lung cancer |
Publisher: | Sage Publications Ltd | Journal: | Therapeutic advances in respiratory disease | ISSN: | 1753-4658 | EISSN: | 1753-4666 | DOI: | 10.1177/1753466620915156 | Rights: | © The Author(s) 2020. This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page (https://us.sagepub.com/en-us/nam/open-access-at-sage). The following publication Wang, F., Meng, F., Wong, S. C. C., Cho, W. C., Yang, S., & Chan, L. W. (2020). Combination therapy of gefitinib and miR-30a-5p may overcome acquired drug resistance through regulating the PI3K/AKT pathway in non-small cell lung cancer. Therapeutic advances in respiratory disease, 14, 1753466620915156, is available at https://doi.org/10.1177/1753466620915156 |
Appears in Collections: | Journal/Magazine Article |
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