Cholesterol synthesis disruption combined with a molecule-targeted drug is a promising metabolic therapy for EGFR mutant non-small cell lung cancer

Luo, Yupeng; Yang, Yunpeng; Peng, Peijian; Zhan, Jie; Wang, Zhihui; Zhu, Zhiquan; Zhang, Zhonghan; Liu, Lin; Fang, Wenfeng; Zhang, Li

doi:10.21037/tlcr-20-812

Cited by 16 publications

(14 citation statements)

References 30 publications

(23 reference statements)

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“…Cholesterol as an important component of lipids contribute to rapid cancer cell growth, metastasis and drug resistance [ 41 ]. Recently, the alteration of cholesterol homeostasis was reported in NSCLC as a result of dysregulation in cholesterol synthesis, uptake or trafficking process [ 17 , 42 ]. In the present study, we found upregulated cholesterol level in both gefitinib-resistant PC-9/GR, H1975 cells and osimertinib-resistant PC-9/OR cells.…”

Section: Discussionmentioning

confidence: 99%

“…Most recently, content of cholesterol is found to be upregulated in NSCLC cells or tumor xenograft models that resistant to the first-generation EGFR-TKIs as the result of increased biosynthesis, uptake and receded efflux. Accumulation of cholesterol is regarded as an important factor of resistance to the first-generation EGFR-TKIs [ 17 – 19 ]. However, the mechanisms of cholesterol confer resistance to EGFR-TKIs are not well-revealed.…”

Section: Introductionmentioning

confidence: 99%

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Cholesterol promotes EGFR-TKIs resistance in NSCLC by inducing EGFR/Src/Erk/SP1 signaling-mediated ERRα re-expression

Pan

Wang

et al. 2022

Mol Cancer

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Background The use of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) brings remarkable benefits for the survival of patients with advanced NSCLC harboring EGFR mutations. Unfortunately, acquired resistance seems to be inevitable and limits the application of EGFR-TKIs in clinical practice. This study reported a common molecular mechanism sustaining resistance and potential treatment options to overcome EGFR-TKIs resistance. Methods EGFR-TKIs resistant NSCLC cells were established and confirmed by MTT assay. Cholesterol content was detected and the promotional function of cholesterol on NSCLC growth was determined in vivo. Then, we identified ERRα expression as the downstream factor of cholesterol-mediated drug resistance. To dissect the regulatory mechanism, we conducted experiments, including immunofluorescence, co-immunoprecipitation, luciferase reporter assay and chromatin immunoprecipitation assay. Results Long-term exposure to EGFR-TKIs generate drug resistance with the characteristic of cholesterol accumulation in lipid rafts, which promotes EGFR and Src to interact and lead EGFR/Src/Erk signaling reactivation-mediated SP1 nuclear translocation and ERRα re-expression. Further investigation identifies ERRα as a target gene of SP1. Functionally, re-expression of ERRα sustains cell proliferation by regulating ROS detoxification process. Lovastatin, a drug used to decrease cholesterol level, and XCT790, an inverse agonist of ERRα, overcome gefitinib and osimertinib resistance both in vitro and in vivo. Conclusions Our study indicates that cholesterol/EGFR/Src/Erk/SP1 axis-induced ERRα re-expression promotes survival of gefitinib and osimertinib-resistant cancer cells. Besides, we demonstrate the potential of lowing cholesterol and downregulation of ERRα as effective adjuvant treatment of NSCLC.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cholesterol promotes EGFR-TKIs resistance in NSCLC by inducing EGFR/Src/Erk/SP1 signaling-mediated ERRα re-expression

Pan

Wang

et al. 2022

Mol Cancer

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“…Similarly, another inhibitor, simvastatin, induced apoptotic cell death in EGFR-mutated, gefitinib-resistant H1975 NSCLC cells by upregulating the pro-apoptotic Bcl-2 family member BIM [119]. Moreover, atorvastatin enhanced the anti-proliferative effect of gefitinib and osimertinib in TKI-sensitive, EGFR-mutated NSCLC models and overcame EGFR gefitinib resistance in H1975 cells [83].…”

Section: Targeting Cholesterol Metabolismmentioning

confidence: 94%

“…Moreover, LDLR (low-density lipoprotein receptor) was highly expressed in EGFRmutated NSCLC cells, suggesting a role of EGFR signaling in upregulating LDLR expression through an AKT-mediated, SREBP1-dependent pathway [83].…”

Section: Cholesterol Metabolismmentioning

confidence: 99%

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

Eltayeb

Monica

Tiseo

et al. 2022

Cells

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Lung cancer is the leading cause of cancer deaths worldwide. Most of lung cancer cases are classified as non-small cell lung cancers (NSCLC). EGFR has become an important therapeutic target for the treatment of NSCLC patients, and inhibitors targeting the kinase domain of EGFR are currently used in clinical settings. Recently, an increasing interest has emerged toward understanding the mechanisms and biological consequences associated with lipid reprogramming in cancer. Increased uptake, synthesis, oxidation, or storage of lipids has been demonstrated to contribute to the growth of many types of cancer, including lung cancer. In this review, we provide an overview of metabolism in cancer and then explore in more detail the role of lipid metabolic reprogramming in lung cancer development and progression and in resistance to therapies, emphasizing its connection with EGFR signaling. In addition, we summarize the potential therapeutic approaches targeting lipid metabolism for lung cancer treatment.

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“…Another study identified a higher expression of low-density lipoprotein receptor (LDLR) mediated by sterol regulatory-element-binding protein 1 (SREBP1) in EGFR -mutant LUAD cells compared to wild type (wt). Combinatorial treatment of ATV and EGFR TKIs resulted in higher inhibition than single treatment, highlighting the importance of lipid biosynthesis in EGFR TKI resistance [ 43 ]. Generally, elevated rates of lipogenesis are a characteristic of numerous tumors while SREBP1-mediated constitutive lipogenesis is one of the main characteristics of EGFR TKI-resistant LUAD cells and might represent a promising druggable target for overcoming the resistance [ 44 , 45 ].…”

Section: Egfr Tki Resistance and Fatty Acid Metabolismmentioning

confidence: 99%

Identification of Targetable Liabilities in the Dynamic Metabolic Profile of EGFR-Mutant Lung Adenocarcinoma: Thinking beyond Genomics for Overcoming EGFR TKI Resistance

et al. 2022

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The use of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) as first-line treatment in patients with lung adenocarcinoma (LUAD) harboring EGFR-activating mutations has resulted in a dramatic improvement in the management of the disease. However, the long-term clinical benefit is inevitably compromised by multiple resistance mechanisms. Accumulating evidence suggests that metabolic landscape remodeling is one of the mechanisms that EGFR-mutant LUAD cells activate, thus acquiring higher plasticity, tolerating EGFR TKI-mediated cytotoxic stress, and sustaining their oncogenic phenotype. Several metabolic pathways are upregulated in EGFR TKI-resistant models modulating the levels of numerous metabolites such as lipids, carbohydrates, and metabolic enzymes which have been suggested as potential mediators of resistance to EGFR TKIs. Moreover, metabolites have been shown to carry signals and stimulate oncogenic pathways and tumor microenvironment (TME) components such as fibroblasts, facilitating resistance to EGFR TKIs in various ways. Interestingly, metabolic signatures could function as predictive biomarkers of EGFR TKI efficacy, accurately classifying patients with EGFR-mutant LUAD. In this review, we present the identified metabolic rewiring mechanisms and how these act either independently or in concert with epigenetic or TME elements to orchestrate EGFR TKI resistance. Moreover, we discuss potential nutrient dependencies that emerge, highlighting them as candidate druggable metabolic vulnerabilities with already approved drugs which, in combination with EGFR TKIs, might counteract the solid challenge of resistance, hopefully prolonging the clinical benefit.

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Cholesterol synthesis disruption combined with a molecule-targeted drug is a promising metabolic therapy for EGFR mutant non-small cell lung cancer

Cited by 16 publications

References 30 publications

Cholesterol promotes EGFR-TKIs resistance in NSCLC by inducing EGFR/Src/Erk/SP1 signaling-mediated ERRα re-expression

Cholesterol promotes EGFR-TKIs resistance in NSCLC by inducing EGFR/Src/Erk/SP1 signaling-mediated ERRα re-expression

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

Identification of Targetable Liabilities in the Dynamic Metabolic Profile of EGFR-Mutant Lung Adenocarcinoma: Thinking beyond Genomics for Overcoming EGFR TKI Resistance

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