Jpn J Cancer Oncol Res | Volume 3, Issue 1 | Research Article | Open Access

Molecular Mechanisms of Rapidly Acquired Resistance to EGFR-TKIs Mediated via the FGF2 Signaling Pathway

Qiong Zhao1*, Chenyu Zhu2, Mingjiao Sun3, Yina Wang4, Yun Zheng1, Wangshan Chen1 and Jing Lin1

1Department of Thoracic Oncology, Shulan Hangzhou Hospital, Affiliated to Shulan International Medical College of Zhejiang Shuren University, China 2Department of Thoracic Oncology, Zhejiang University, China 3Department of Thoracic Oncology, Cancer Institute of Hangzhou Cancer Hospital, China 4Department of Medical Oncology, The First Affiliated Hospital of Zhejiang University, China

*Correspondance to: Qiong Zhao 

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Abstract

Background: This study aimed to investigate the mechanisms of rapidly acquired resistance to Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors (EGFR-TKIs) mediated by the Fibroblast Growth Factor 2 (FGF2) signaling pathway and to provide evidence that treatment with combinations of EGFR and FGFR inhibitors may be a promising strategy for some patients who are resistant to EGFR inhibitors. Methods: For this purpose, PC-9 cell lines (non-small cell lung carcinoma cell line harboring exon 19 del in EGFR) with FGF2 silencing or overexpression were established and FGF2 expression in these cells was determined to determine acquired resistance to EGFR-TKIs. The proliferation, migration, and invasion of the resistant cell lines were assessed. A whole-genome Affymetrix 3' IVT microarray chip was used to detect the expression of downstream genes in the resistant cell lines. Results: The results revealed that the viability of the PC-9 cells increased with FGF2 overexpression in the presence of exogenous FGF2, which indicated that exogenous FGF2 assisted in inducing rapidly acquired resistance to EGFR-TKIs in FGF2-overexpressing PC-9 cells. Cell biology assays further demonstrated EGFR-TKI-resistant behavior, such as a decrease in apoptosis, an increase in proliferation, and the enhancement of the invasive and migratory ability of PC-9-FGF2- overexpressing cells incubated with exogenous FGF2. Microarray analysis suggested that the PI3K-AKT signaling pathway may play an important role in FGF2-mediated rapidly acquired drug resistance to EGFR-TKIs. Conclusion: On the whole, in this study, a cell model of FGF2-mediated rapidly acquired resistance to EGFR-TKIs in an NSCLC cell line was successfully constructed. This may prove to be the basis for further investigations on the molecular mechanisms of FGF2-mediated rapidly acquired resistance to EGFR-TKIs. Besides, this study provides evidence that the PI3K-AKT signaling pathway may play an important role in the pathogenesis of FGF2-mediated rapidly acquired drug resistance to EGFR-TKIs.

Keywords:

Acquired resistance; EGFR-TKIs; FGF2 signaling pathway; PI3K-AKT signaling pathway; NSCLC

Citation:

Zhao Q, Zhu C, Sun M, Wang Y, Zheng Y, Chen W, et al. Molecular Mechanisms of Rapidly Acquired Resistance to EGFR-TKIs Mediated via the FGF2 Signaling Pathway. Jpn J Cancer Oncol Res. 2020; 3(1): 1008.

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