Figure 1.

Overview of the metabolic remodeling in EGFR-mutant LUAD and the proposed treatment strategies for circumventing the EGFR TKI resistance. EGFR TKI-resistant LUAD cells secrete lactate, which is incorporated by CAFs located in TME, leading to overproduction of HGF ligands and subsequent activation of MET signaling and its downstream oncogenic effectors such as Ras/Raf/MEK/Erk signaling pathway. Moreover, the FASN-mediated EGFR palmitoylation allows the maintenance of EGFR constitutive signaling in EGFR TKI-resistant cells. Abrogation of palmitic acid synthesis using the anti-obesity drug orlistat (FASN inhibitor) promotes EGFR degradation. The use of statins such as ATV significantly downregulates the cholesterol levels, decreasing glucose uptake and lipogenesis simultaneously in EGFR-mutant LUAD. Further restriction of fatty acid synthesis by inhibiting SREBP1 using PF-429242 impairs both the levels of FASN and LDLR. Interestingly, blocking the PDHK1-mediated phosphorylation of PDH by treating EGFR-mutant LUAD cells with DCA shifts the glucose metabolism towards oxidative phosphorylation, preventing the accumulation of lactate, which has been correlated with EGFR TKI resistance. Furthermore, EGFR TKI-resistant cells have elevated levels of glutathione, the master antioxidant, thus efficiently scavenging ROS, escaping oxidative stress and cell death. Treatment with drugs such as epalrestat and BSO reduces glutathione synthesis, allowing ROS accumulation which eventually leads to ROS-mediated cell death in EGFR TKI-resistant models. Finally, epigenetic downregulation of SDH activity by miR-147b induces TCA cycle arrest and increased levels of succinate in EGFR TKI-tolerant cells. Abbreviations: CAF, cancer-associated fibroblast; TME, tumor microenvironment; MCT4, monocarboxylate 4; HGF, hepatocyte growth factor; LDLR, low-density lipoprotein receptor; LDL, low-density lipoprotein; EGFR, epidermal growth factor receptor; GLUT-3, glucose transporter 3; Cav-1, caveolin-1; G6P, glucose 6-phosphate; TCA cycle, tricarboxylic acid cycle; SDH, succinate dehydrogenase; ATV, atorvastatin; FASN, fatty acid synthase; PI3K, phosphoinositide 3-kinase; mTORC1, mTOR complex 1; ROS, reactive oxygen species; DCA; dichloroacetate; PDH, pyruvate dehydrogenase; PDHK1, pyruvate dehydrogenase kinase 1; Acetyl-CoA, acetyl coenzyme A; LDHA, lactate dehydrogenase A; SRBP1, sterol regulatory-element-binding protein 1; BSO, buthionine sulfoximine; BCAT1, branched-chain amino acid aminotransferase 1.