ArticleTranslational lung cancer research2026
LPIN2 contributes to tyrosine kinase inhibitor resistance via activation of PI3K pathway.
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. Not yet cited in PubMed.
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Abstract
Background: Acquired resistance to tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) is a critical clinical barrier. While metabolic reprogramming is implicated in target-independent resistance, the specific role of triglyceride (TG) synthesis remains unclear. Objective: This study aims to systematically elucidate the precise role and underlying mechanisms of LPIN2-mediated lipid metabolic reprogramming in TKI resistance, and to explore potential metabolic-targeted combination therapies for NSCLC. Methods: Osimertinib-resistant (PC-9 OR) and alectinib-resistant (NCI-H3122 ALR) cell lines were established via a dose-escalation strategy. The resistant cells were then compared with their original sensitive cells under both drug-present and drug-withdrawn conditions. Metabolomic liquid chromatography-mass spectrometry (LC-MS) and transcriptomic analyses revealed shared differential features, which were selected as candidate key metabolic enzymes in TKI resistance. From this pathway, LPIN2 was selected as a consistently upregulated key enzyme for validation. The Results: LPIN2 was identified as a key driver of TKI resistance in NSCLC, with its mRNA and protein levels significantly upregulated (~2-fold) in osimertinib-resistant (PC-9 OR) and alectinib-resistant (NCI-H3122 ALR) cells. CRISPR/Cas9-mediated LPIN2 knockout restored TKI sensitivity, displaying oncogene-specific magnitudes of reduction in the half-maximal inhibitory concentration (IC Conclusions: LPIN2 contributes to TKI resistance in NSCLC through a novel LPIN2-TG metabolic node that is functionally associated with PI3K-AKT signaling: it enhances TG biosynthesis and lipid droplet accumulation, thereby indirectly modulating the PI3K-AKT pathway to inhibit apoptosis. Targeting this axis reverses TKI resistance
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