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

Abstract

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.

Keywords: EGFR; EGFR-TKI resistance; lipid metabolism; lung cancer.

Figure 1

Lipid metabolism. Endogenous lipid synthesis is mediated by the accumulation of citrate in the cytosol and activation of the key lipogenic enzymes. Lipids (palmitate, cholesterol, DAG, MAG, and phospholipids) participate in multiple functions within the cell or are stored in lipid droplets. Sphingolipids, such as sphingomyelin, are converted to ceramide by sphingomyelinase, and ceramide is then converted into sphingosine-1-phosphate (S-1-P), which is involved in regulating many cellular functions. Exogenous uptake of fatty acids is mediated by different transporters (FATP and CD36). Fatty acid oxidation is mediated by transport of FAs into mitochondria through CPT1/2. Abbreviations: GLUTs: glucose transporters, TCA: tricarboxylic acid cycle, FAO: fatty acid oxidation, DAG: diacylglycerol, TAG: triacylglycerol, ACLY: ATP citrate lyase, ACC: acetyl-CoA carboxylase, FASN: fatty acid synthase, SCD: stearoyl-CoA desaturase, FAs: fatty acids, HMGCR: 3-hydroxy-3-methylglutaryl coenzyme A reductase, SMase: sphingomyelinase, CMase: ceramidase, SPK: sphingosine kinase, FATP: fatty acid transport protein, CPT1/2: carnitine palmitoyl transferase 1/2.

Figure 2

Modulation of lipid metabolism by EGFR signaling. EGFR induces lipogenesis activating the PI3K/AKT and MAPK pathways, which converge on mTOR-dependent inhibition of Lipin1. This event allows the translocation of SREBP into the nucleus. SREBP acts as a transcription factor for different genes involved in lipid metabolism, such as ACLY, ACC, FASN, SCD1 (FA synthesis), HMGCR, and LDLR (cholesterol synthesis and uptake). EGFR directly phosphorylates SCD1 at tyrosine 55 and promotes its stabilization, increasing MUFAs production. MUFAs and cholesterol contribute to the activation of EGFR signaling through modulating cell membrane stability and fluidity.

Figure 3

Targeting lipid metabolism in lung cancer. Inhibitors of lipid synthesis and oxidation used in preclinical studies in lung cancer models.