Targeting AKR1 Overcomes Acquired Resistance To EGFR-TKIs In Lung Adenocarcinomas

Lung adenocarcinomas harboring activating mutations in EGFR frequently respond to EGFR-targeted tyrosine kinase inhibitors(TKIs),such as gefitinib,erlotinib and osimertinib,but the resistance to these drugs invariably occurs and the disease relapses.In this study,we identify that lung adenocarcinomas acquire resistance to EGFR-TKIs depending on aldo-keto reductase(AKR)upregulation and that AKR1 elicits the effect by facilitating reactive oxygen species(ROS)-reactive carbonyl species(RCS)metabolic pathway.AKR1 is upregulated in EGFR-TKI-resistant cells;this leads to a stem cell-like(CSC)and epithelial-mechanchymal transition(EMT),endowing the cell ability to withstand the drug stress;also this renders these cells depend on and addicted to AKR1.Targeting the molecule reverses the acquired CSC/EMT properties and overcomes the resistance;moreover suppression of AKR1 resensitizes the tumor response to TKIs and abrogates the resistance in vitro and in vivo.Mechanically AKR1-induced upregulation of SOD2,as well as AKR1 itself,mitigated the EGFR-TKI-induced oxidative and carbonyl stress in the cancer cells and impart resistance against EGFR-TKIs.A better understanding of metabolic mechanism underlying AKR1-dependent EGFR-TKI resistance will deepen the knowledge of drug resistance and metabolic rewiring and help to design novel pharmacological strategies to overcome the resistance.