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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

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 endoge...

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Autores principales: Wang, Fengfeng, Meng, Fei, Wong, Sze Chuen Cesar, Cho, William C.S., Yang, Sijun, Chan, Lawrence W.C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: SAGE Publications 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303773/
https://www.ncbi.nlm.nih.gov/pubmed/32552611
http://dx.doi.org/10.1177/1753466620915156
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author Wang, Fengfeng
Meng, Fei
Wong, Sze Chuen Cesar
Cho, William C.S.
Yang, Sijun
Chan, Lawrence W.C.
author_facet Wang, Fengfeng
Meng, Fei
Wong, Sze Chuen Cesar
Cho, William C.S.
Yang, Sijun
Chan, Lawrence W.C.
author_sort Wang, Fengfeng
collection PubMed
description 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.
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spelling pubmed-73037732020-06-26 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 Wang, Fengfeng Meng, Fei Wong, Sze Chuen Cesar Cho, William C.S. Yang, Sijun Chan, Lawrence W.C. Ther Adv Respir Dis Original Research 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. SAGE Publications 2020-06-18 /pmc/articles/PMC7303773/ /pubmed/32552611 http://dx.doi.org/10.1177/1753466620915156 Text en © The Author(s), 2020 https://creativecommons.org/licenses/by-nc/4.0/ 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).
spellingShingle Original Research
Wang, Fengfeng
Meng, Fei
Wong, Sze Chuen Cesar
Cho, William C.S.
Yang, Sijun
Chan, Lawrence W.C.
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
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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_short 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
title_sort 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
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303773/
https://www.ncbi.nlm.nih.gov/pubmed/32552611
http://dx.doi.org/10.1177/1753466620915156
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