ArticleTranslational lung cancer research2026
PKC-iota drives EGFR-TKI resistance in EGFR-mutated NSCLC by phosphorylating FASN to reprogram lipid metabolism.
Article in Translational lung cancer research, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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1 citing paper in PubMed.
- LPIN2 contributes to tyrosine kinase inhibitor resistance via activation of PI3K pathway.Translational lung cancer research · 2026Article
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10 authors.
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Abstract
Background: Non-small cell lung cancer (NSCLC) remains a significant challenge to global public health issues. However, epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) resistance inevitably occurs in treating EGFR-mutant NSCLC, and the underlying metabolic mechanisms remain unclear. The objective of our study is to explore the regulatory mechanisms of the atypical protein kinase C-iota (PKC-iota) in reprogramming lipid metabolism and whether this regulation contributes to the EGFR-TKI resistance in EGFR-mutant NSCLC. Methods: We use mass spectrometry (MS), co-immunoprecipitation, proximity ligation assays and molecular docking to investigate the interaction of PKC-iota and fatty acid synthase (FASN). Subsequently, Western blot assay, MS, lipid staining, membrane fluidity assay, and membrane proteins assay were performed to investigate how PKC-iota regulated the lipid metabolism by FASN. We established four types of transiently transfected H1975 and PC9 cell lines. These models were then employed in a series of assays-including Cell Counting Kit-8 (CCK-8), flow cytometry, cell counting, and colony formation-to evaluate changes in cell proliferation and EGFR-TKIs sensitivity. Four types of stably transfected H1975 cell lines were inoculated into female BALB/c nude mice, then the tumorigenicity and osimertinib sensitivity of the cell groups were analyzed. Finally, we collected 45 tumor samples of EGFR-mutated NSCLC patients to examine the clinical significance of the PKC-iota/FASN axis. Results: We observed that PKC-iota physically interacted with FASN and stabilized the FASN protein by phosphorylating it and inhibiting its ubiquitin-proteasome degradation at the post-transcriptional level. PKC-iota enhanced short/medium-chain and unsaturated fatty acid synthesis via FASN, and the PKC-iota/FASN axis increased membrane fluidity to inhibit lipid raft-mediated EGFR endocytosis and degradation while upregulating EGFR membrane localization and promoting EGFR overactivation in NSCLC. The increased tumor growth and EGFR-TKI resistance induced by the PKC-iota/FASN axis were observed both Conclusions: Our study elucidates a mechanism of EGFR-TKI resistance mediated by the PKC-iota/FASN axis through reprogramming lipid metabolism in EGFR-mutated NSCLC, which provides a novel therapeutic target for overcoming EGFR-TKI resistance and improving the prognosis of EGFR-mutated NSCLC patients.
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