Lipidomics reveals that sustained SREBP-1-dependent lipogenesis is a key mediator of gefitinib-acquired resistance in EGFR-mutant lung cancer

Abstract

Patients with EGFR mutations in non-small cell lung cancer (NSCLC) have been greatly benefited from gefitinib, however, the therapeutic has failed due to the presence of acquired resistance. In this study, we show that gefitinib significantly induces downregulation of Sterol Regulator Element Binding (SREBP1) in therapy-sensitive cells. However, this was not observed in EGFR mutant NSCLC cells with acquired resistance. Lipidomics analysis showed that gefitinib could differently change the proportion of saturated phospholipids and unsaturated phospholipids in gefitinib-sensitive and acquired-resistant cells. Besides, levels of ROS and MDA were increased upon SREBP1 inhibition and even more upon gefitinib treatment. Importantly, inhibition of SREBP1 sensitizes EGFR-mutant therapy-resistant NSCLC to gefitinib both in vitro and in vivo models. These data suggest that sustained de novo lipogenesis through the maintenance of active SRBEP-1 is a key feature of acquired resistance to gefitinib in EGFR mutant lung cancer. Taken together, targeting SREBP1-induced lipogenesis is a promising approach to overcome acquired resistance to gefitinib in EGFR-mutant lung cancer.

A Novel Small-Molecule Inhibitor of SREBP-1 Based on Natural Product Monomers Upregulates the Sensitivity of Lung Squamous Cell Carcinoma Cells to Antitumor Drugs

“…Treatment of MSI-1 not only inhibited the downstream genes (including Fasn, Acc, Acly, and Scd) of SREBP-1 but also inhibited the glycolysis-related biochemical indices (glucose uptake, lactate and ATP production, and LDH) and EMT-related factors. Increasing evidence have indicated that SREBP-1 is a major regulator of lipid metabolism (especially fatty acid synthesis) and a key factor in cell proliferation and microenvironment regulation, especially drug resistance ( Chen et al, 2018 ; Talebi et al, 2018 ; Xu et al, 2021 ). In this study, we found and confirmed the effect of MSI-1 on SREBP-1, and MSI-1 could upregulate the sensitivity of LUSC cells to antitumor drugs by acting on SREBP-1.…”

ApoM regulates PFKL through the transcription factor SREBF1 to inhibit the proliferation, migration and metastasis of liver cancer cells

“…Using a bioinformatics analysis, the present study demonstrated that the upregulation of SREBF1 gene expression levels was more significant than that of SREBF2 in a low-ApoM gene expression group, compared with that in an ApoM high-expression group ( Table SI ). Previous studies have further highlighted that SREBF1 regulates lipid metabolism and it may provide energy for tumor cells through the lipogenesis pathway ( 28 ). In terms of glycolysis, it has been reported that SREBF1 and PKM2 are closely associated with tumor growth; however, the association between SREBF1 and PFKL has remained to be elucidated ( 29 ).…”

Reprogramming of Lipid Metabolism in Lung Cancer: An Overview with Focus on EGFR-Mutated Non-Small Cell Lung Cancer

“…Sensitivity to EGFR inhibition was restored by genetic knockdown of SREBP1 in vitro and in vivo, suggesting SREBP1/ACC/FASN targeting as a valuable strategy to overcome acquired resistance to EGFR TKIs. Moreover, Xu et al [50] showed that the constitutive SREBP1-mediated activation of the lipogenic pathway is a key mediator of gefitinib-acquired resistance in EGFR mutant lung cancer, and targeting SREBP1 with fatostatin restored gefitinib sensitivity in resistant NSCLC in both in vitro and in vivo models.…”