Decreased human antigen R expression confers resistance to tyrosine kinase inhibitors in epidermal growth factor receptor-mutant lung cancer by inhibiting Bim expression

Yao,Yunfeng; Chu,Huili; Wang,Jun; Wang,Baocheng

doi:10.3892/ijmm.2018.3835

Decreased human antigen R expression confers resistance to tyrosine kinase inhibitors in epidermal growth factor receptor-mutant lung cancer by inhibiting Bim expression

Authors:
- Yunfeng Yao
- Huili Chu
- Jun Wang
- Baocheng Wang
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Affiliations: Institute of Post‑Graduate, The Second Military Medical University, People's Liberation Army, Shanghai 200433, P.R. China, Department of Oncology, General Hospital, Jinan Command of The People's Liberation Army, Jinan, Shandong 250031, P.R. China, Institute of Post‑Graduate, The Second Military Medical University, People's Liberation Army, Shanghai 200433, P.R. China
Published online on: August 22, 2018 https://doi.org/10.3892/ijmm.2018.3835
Pages: 2930-2942

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Abstract

Primary resistance to epidermal growth factor receptor‑tyrosine kinase inhibitors (EGFR‑TKIs) is an obstacle for the treatment of non‑small cell lung cancer (NSCLC); however, the associated mechanisms are not well understood. Studies have reported that Bim expression levels may be associated with the efficacy of EGFR‑TKI treatment in NSCLC patients harboring EGFR mutations. Human antigen R (HuR) regulates the mRNA and protein expression of target genes, including certain B‑cell lymphoma 2 family members. The present study investigated whether HuR mediates resistance to EGFR‑TKIs via the regulation of Bim. The results demonstrated that decreased levels of HuR and Bim protein expression are associated with primary resistance to EGFR‑TKIs and reduced median progression‑free survival in NSCLC patients. In vitro assays also revealed that knockdown of HuR resulted in primary EGFR‑TKI resistance and reduced gefitinib‑induced apoptosis in HCC827 cells by decreasing Bim expression. Furthermore, elevated HuR expression restored gefitinib sensitivity and enhanced gefitinib‑induced apoptosis in H1650 cells by increasing Bim expression. In vivo, it was further demonstrated that overexpression of HuR was able to restore the gefitinib sensitivity of H1650 cells. Therefore, altered HuR/Bim expression is proposed to be a novel mechanism of EGFR‑TKI resistance in NSCLC.

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