Targeting AKR1B1 inhibits glutathione de novo synthesis to overcome acquired resistance to EGFR-targeted therapy in lung cancer

Abstract

AKR1B1 boosts glutathione de novo synthesis as a metabolic mechanism driving resistance to EGFR-targeted therapy in mouse models of lung cancer.

Cancer cell-autonomous cGAS-STING response confers drug resistance

“…Cell lines which are resistant to erlotinib (HCC827ER), gefitinib (HCC827GR), and osimertinib (HCC827OR and H1975OR1–5) were established, maintained, and authenticated as schematized (Supplementary Fig. 1A) and previously described (9–11). The cells were cultured in RPMI 1640 medium (Gibco, USA) containing 10% FBS, 1% GlutaMAX, and 1% penicillin-streptomycin at 37 °C with 5% CO2.…”

“…Resistance is one of the biggest challenges for cancer treatment (8). Based on our in vitro and in vivo cancer targeted therapy resistance models (9–11), we repeatedly and curiously noticed that an activated rather than suppressed status was achieved in cGAS-STING signaling when these cancer cells acquired resistance to therapeutic drugs. We hypothesized that the cells that can upregulate cGAS-STING signaling would acquire the ability to cope with drug stress and evolve drug resistance.…”

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

“…Dichloroacetate PDHK inhibitor Induction of Acetyl-CoA formation [26] Atorvastatin CAV-1/GLUT-3 inhibitor Inhibition of glucose uptake and cholesterol synthesis [30] PF-429242 SREBP1 inhibitor Inhibition of lipid synthesis [31] Orlistat FASN inhibitor Inhibition of EGFR palmitoylation [32] Epalrestat AKR1B1 inhibitor Inhibition of GSH synthesis [33] PiperlongumineAuranofin ROS inducing agent Induction of oxidative stress [34] Buthionine sulfoximine GSH synthesis inhibitor Inhibition of GSH synthesis [34] 1,25D VDR agonist Inhibition of stemness phenotype [35] AZ12756122 FASN inhibitor Inhibition of stemness phenotype [36] Abbreviations: PDHK, pyruvate dehydrogenase kinase; Acetyl-CoA, acetyl coenzyme A; CAV-1, caveolin-1; GLUT-3, glucose transporter-3; FASN, fatty acid synthase; EGFR, epidermal growth factor receptor; SREBP1, sterol regulatory-element-binding protein 1; AKR1B1, aldo-keto reductase family 1 member B1; GSH, glutathione; ROS, reactive oxygen species; 1,25D, 1,25-dihydroxyvitamin D3; VDR, vitamin D receptor.…”

“…Another study performed RNA sequencing analysis and immunoblotting in EGFR TKI-resistant HCC827 and H1975 models, identifying the upregulation of aldo-keto reductase family 1 member B1 (AKR1B1). Downregulation of AKR1B1 restored the sensitivity to osimertinib both in vitro and in vivo, while its ectopic overexpression rescued the resistant phenotype, revealing a crucial role of AKR1B1 in the occurrence of resistance [ 33 ]. Transcriptomic and metabolic comparisons of the models identified GSH metabolism as one of the most altered pathways.…”

“…Disruption of AKR1B1, either genetically or due to epalrestat, an approved antidiabetic agent, inhibited the increase of GSH. The combination of epalrestat and either gefitinib or osimertinib therefore resulted in the restriction of tumor growth and delayed relapse by abrogating the axis of AKR1B1/p-STAT3/SLC7A11 in resistant models [ 33 ].…”