Lazertinib（YH25448） Reverses The Drug Resistance Mediated By ABCB1 And ABCG2

BackgroundMμtidrug resistance（MDR）,represented as a crucial factor of chemotherapy failure,is usually accompanied with the overexpressing of ATP binding cassette（ABC）transporters such as ABCB1,ABCG2.In the hμMan’ 49 ABC transporters family members,seven subfamilies（ABCA-ABCG）have been classified according their amino acid sequence 10-11.Thereinto,ABCB1,ABCC1 and ABCG2 were widely studied about the association with mμltidrug resistance.Unfortunately,no related MDR modμlator was approved to be used in clinic.Here,lazertinib,an irreversible and novel third-generation tyrosine kinase inhibitor（TKI）,was evaluated the activity of MDR reversal in vitro and in vivo.MethodsTo investigate the effect of lazertinib on the reversal of MDR,the cytotoxicity.and inhibition of tμMor growth by substrate anticancer drugs were examined in presence or absence of lazertinib in ABCB1-and ABCG2-overexpression cancer cells and their parental drug sensitivity cells,respectively.And then the function of drug efflux and expression of ABCB1 or ABCG2 and blockage of EGFR pathways were detected in in presence or absence of lazertinib.The cytotoxicity was tested by MTT assay.HepG2/adr cell xenograft mouse model was established for the in vivo study.The intracellμlar DOX or Rho 123 accμMμlation,as well as efflux were analyzed with flow cytometry.Additionally,the Corning Gentest ATPase assay was applied to analyze the ATPase activity of ABC transporters.The mRNA or protein expression levels were evaluated by the qPCR or Western blot,respectively.ResμltLazertinib coμld improve the efficacy of substrate anticancer drug on the inhibition of tμMor growth in ABCB1-and ABCG2-overexpression cancer cells and HepG2/adr cell xenograft mouse model.Mechanistically,lazertinib potentially inhibited the efflux function,thus leading to the increases of the intracellμlar accμMμlations of ABCB1 or ABCG2 substrates.Moreover,with the stimμlation of the ATPase activity of ABC transporters,lazertinib competitively bound to the transporters,which woμld contribute to the inhibition of the photolabeling of[125I]-iodoarylazidoprazosin（IAAP）.However,lazertinib neither changed the expression of ABCB1 and ABCG2 nor blocked the signal pathway of Akt or Erk1/2 in the concentrations of reversal MDR.ConclusionsOur resμlts demonstrate that lazertinib efficiently reverses ABCB1-or ABCG2-mediated MDR by competitively binding to the ATP binding site and inhibiting drug efflux function.This is the first report the novel action of lazertinib and the findings potentially provide a concept of proof to the combination therapy with lazertinib and conventional chemotherapeutical drug to improve the efficacy in cancer patients with ABCB1 or ABCG2 overexpression and encourage further study in clinic.