LPIN1 Induces Gefitinib Resistance in EGFR Inhibitor-Resistant Non-Small Cell Lung Cancer Cells

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 fac...

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Bibliographic Details
Published in:Cancers 2022-04, Vol.14 (9), p.2222
Main Authors: Cho, Jung Hee, You, Yeon-Mi, Koo, Han, Lee, Dong Chul, Yeom, Young Il, Park, Kyung Chan
Format: Article
Language:English
Subjects:
Cancer therapies
Cell activation
Cell growth
Cell survival
Diglycerides
Drug resistance
Epidermal growth factor
Epidermal growth factor receptors
Fatty acids
Gefitinib
Genomes
Kinases
Lipids
Lung cancer
Metabolism
Mutants
Mutation
NF-κB protein
Non-small cell lung carcinoma
Patients
Phosphatase
Plasmids
Protein kinase C
Protein-tyrosine kinase
Proteins
Reagents
RNA-mediated interference
Small cell lung carcinoma
Software
Tumorigenesis
Xenografts
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Summary: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.
ISSN:2072-6694
2072-6694
DOI:10.3390/cancers14092222