J Cancer Prev.  2019 Dec;24(4):217-223. 10.15430/JCP.2019.24.4.217.

Overcoming the Intrinsic Gefitinib-resistance via Downregulation of AXL in Non-small Cell Lung Cancer

• Jeong I
• Song J
• Bae SY
• Lee SK

• KMID: 2468811
• DOI: http://doi.org/10.15430/JCP.2019.24.4.217

Abstract

BACKGROUND
Resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib, is a limited factor in the treatment of non-small-cell lung cancer (NSCLC) patients. Therefore, ongoing studies are trying to identify EGFR-TKIs-resistant mechanisms and to discover novel therapeutic strategies and targets for NSCLC treatment.
METHODS
In the present study, the possibility of overcoming intrinsic gefitinib-resistance was examined by regulating the expression of AXL. A natural product-derived antitumor agent, yuanhuadine (YD) was employed to modulate the expression of AXL in the cells.
RESULTS
Treatment with YD effectively downregulated AXL expression in AXL-overexpressed gefitinib-resistant H1299 cells. The combination of gefitinib and YD exhibited a synergistic grwoth-inhibitory activity in H1299 cells by downregulation of AXL expression.
CONCLUSIONS
Based on these findings, AXL was found to be a promising therapeutic target to overcome the intrinsic resistance to gefitinib in NSCLC. Furthermore, YD is able to effectively regulate the expression of AXL and thus it may be applicable as a potential lead compound for the treatment of gefitinib-resistant NSCLC.

Keyword

axl receptor tyrosine kinase; Non-small-cell lung cancer; Gefitinib; Yuanhuadine; Drug resistance

MeSH Terms

Carcinoma, Non-Small-Cell Lung*
Down-Regulation*
Drug Resistance
Humans
Lung Neoplasms
Protein-Tyrosine Kinases
Receptor, Epidermal Growth Factor
Protein-Tyrosine Kinases
Receptor, Epidermal Growth Factor