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Suppressed expression of Cbl‐b by NF‐κB mediates icotinib resistance in EGFR‐mutant non‐small‐cell lung cancer
Author(s) -
Zhang Tieqiong,
Zheng Chunlei,
Hou Kezuo,
Wang Jinyao,
Zhang Ye,
Fan Yibo,
Zhao Huan,
Qu Xiujuan,
Liu Yunpeng,
Kang Jian,
Che Xiaofang,
Hu Xuejun
Publication year - 2019
Publication title -
cell biology international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.932
H-Index - 77
eISSN - 1095-8355
pISSN - 1065-6995
DOI - 10.1002/cbin.11026
Subject(s) - downregulation and upregulation , cancer research , ubiquitin ligase , epidermal growth factor receptor , gene knockdown , protein kinase b , biology , chemistry , cell culture , ubiquitin , signal transduction , cancer , microbiology and biotechnology , gene , biochemistry , genetics
Although epidermal growth factor receptor tyrosine kinase inhibitor (EGFR‐TKI) could greatly improve the prognosis of NSCLC patients harboring activating EGFR mutations, drug resistance still remains a major obstacle to successful treatment. Our previous study found that the EGFR‐TKI icotinib could upregulate the expression of Casitas‐B‐lineage lymphoma protein‐B (Cbl‐b), an E3 ubiquitin ligase. In the present study, we aimed to clarify the potential role of Cbl‐b in the resistance to icotinib, and the underlying mechanisms using EGFR‐mutant cell lines. We found that icotinib inhibited the proliferation of mutant‐EGFR NSCLC cells (PC9 and HCC827), and upregulated the expression of Cbl‐b at both the protein and mRNA levels. Cbl‐b knockdown decreased the sensitivity of PC9 and HCC827 cells to icotinib, and partially restored icotinib‐inhibited AKT activation in PC9 cells. On the contrary, Cbl‐b overexpression could partly reverse the drug resistance in PC9 icotinib‐resistant cells (PC9/IcoR). Moreover, overexpressing p65, the main member of transcription factor NF‐κB family, reversed the icotinib‐mediated upregulation of Cbl‐b. Collectively, these data suggest that icotinib could upregulate Cbl‐b mediated by NF‐κB inhibition, and Cbl‐b contribute to the icotinib sensitivity in EGFR‐mutant NSCLC cells. This study highlights that low expression of Cbl‐b might be the key obstacles in the efficacy of icotinib therapy.