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

Fengfeng Wang, Fei Meng, Sze Chuen Cesar Wong, William C.S. Cho, Sijun Yang, Lawrence W.C. Chan

Research output: Journal article publicationJournal articleAcademic researchpeer-review

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.

Original languageEnglish
JournalTherapeutic Advances in Respiratory Disease
Volume14
DOIs
Publication statusPublished - 18 Jun 2020

Keywords

  • combination therapy
  • drug resistance
  • epidermal growth factor receptor
  • gefitinib
  • miR-30a-5p
  • non-small cell lung cancer

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Pharmacology (medical)

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