Auranofin reverses acquired resistance to osimertinib in non-small cell lung cancer / 中国药理学通报

ABSTRACT

Aim To investigate the role of auranofin in reversing acquired resistance to osimertinib in non-small cell lung cancer. Methods Osimertinib-sensi-tive NSCLC cell lines HI975 and PC9 were used to establish osimertinib-resistant NSCLC cell lines HI975/OR and PC9/OR. An FDA approved library of 1470 FDA drugs was used to high-throughput screen the reversal agents of acquired resistant of osimertinib by CCK-8. Compusyn was used to calculate the combination index of osimertinib and auranofin to determine the optimal dose of drug combination. CCK-8, EdU, flow cytometry and Transwell experiments were used to detect osimertinib, auranofin and the combination drug effect on proliferation, apoptosis, migration and invasion of osimertinib acquired NSCLC cell lines. RNA-sequencing was applied to screen differentially expressed mRNAs in osimertinib treatment alone and osimertinib combined with auranofin treatment group. qRT-PCR and western blot were employed to validate the selected gene expression and protein expression. Results Compared with osimertinib sensitive cell lines H1975 and PC9, H1975/OR and PC9/OR showed significantly higher cell viability and lower apoptosis rate after osimertinib treatment. The resistance index was 70. 31 and 136. 99, respectively. In FDA approved 1470 drug library, only auranofin could enhance the sensitivity of osimertinib in H1975/OR and PC9/OR. When 1 μmol • L