吉非替尼
表皮生长因子受体
癌症研究
肺癌
小发夹RNA
酪氨酸激酶抑制剂
抗药性
癌症
生物
细胞培养
药理学
医学
肿瘤科
基因敲除
内科学
遗传学
作者
Jung Hee Cho,Yeon-Mi You,Han Koo,Dong Chul Lee,Young Il Yeom,Kyung Chan Park
出处
期刊:Cancers
[MDPI AG]
日期:2022-04-29
卷期号:14 (9): 2222-2222
被引量:2
标识
DOI:10.3390/cancers14092222
摘要
Drug resistance limits the efficacy of targeted therapies, including tyrosine kinase inhibitors (TKIs); however, a substantial portion of the drug resistance mechanisms remains unexplained. In this study, we identified LPIN1 as a key factor that regulates gefitinib resistance in epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) cells. Unlike TKI-sensitive HCC827 cells, gefitinib treatment induced LPIN1 expression and increased diacylglycerol concentration in TKI-resistant H1650 cells, followed by the activation of protein kinase C delta and nuclear factor kappa B (NF-κB) in an LPIN1-dependent manner, resulting in cancer cell survival. Additionally, LPIN1 increased the production of lipid droplets, which play an important role in TKI drug resistance. All results were recapitulated in a patient-derived EGFR-mutant NSCLC cell line. In in vivo tumorigenesis assay, we identified that both shRNA-mediated depletion and pharmaceutical inhibition of LPIN1 clearly reduced tumor growth and confirmed that gefitinib treatment induced LPIN1 expression and LPIN1-dependent NF-κB activation (an increase in p-IκBα level) in tumor tissues. These results suggest an effective strategy of co-treating TKIs and LPIN1 inhibitors to prevent TKI resistance in NSCLC patients.
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