High Expression of FOXC1 in EGFR-TKI Resistant Non-Small Cell Lung Cancer

[Speaker] Yu-Hsuan Yeh:1
[Co-author] Pin-Jyun Chen:1, Jin-Yuan Shih:2, Ching-Chow Chen:1
1:Department of Pharmacology, College of Medicine, National Taiwan University, Taiwan, 2:Department of Internal Medicine, National Taiwan University Hospital, Taiwan

Forkhead Box C1 (FOXC1) is a transcription factor associated with non-small cell lung cancer (NSCLC). EGFR tyrosine kinase inhibitors (EGFR-TKIs) have been shown good therapeutic effect on NSCLC patients with EGFR activating mutations. However, acquired resistance develops after several months of treatment. Whether FOXC1 is associated with the resistance of EGFR-TKIs was investigated.
Gefitinib (Iressa)-resistant HCC827/IR and AZD9291-resistant H1975/AR cell lines were established by exposing sensitive cell lines to gefitinib and AZD9291, respectively. Gene knockdown was performed by shRNA, while gene overexpression was achieved by proper plasmid transfection. Changes in protein and mRNA levels were detected by Western blotting and qPCR. Drug sensitivity was evaluated by clonogenic assay. Cell motility and cancer stem cell-like properties were measured by transwell migration assay and sphere-forming assay.
High expression of FOXC1 was found in TKI-resistant HCC827/IR and H1975/AR cells. Knockdown of FOXC1 restored drug sensitivity and decreased the cell proliferation, migration and sphere-forming ability. Conversely, overexpression of FOXC1 led to an increase in cell migration and sphere-forming ability. In addition, FOXC1 knockdown showed an upregulation of RhoGDI2. Further analysis demonstrated that knockdown of RhoGDI2 in parental cell lines increased cell migration and sphere-forming ability.
Our findings support that FOXC1 mediates sensitivity and resistance of EGFR-TKIs, and RhoGDI2 might be a downstream of FOXC1 to be involved in EGFR-TKI resistance in NSCLC.

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