Osimertinib (OSI, also known as AZD9291) is the newest FDA-approved epidermal 
growth factor receptor (EGFR) tyrosine kinase inhibitor for non-small cell lung 
cancer (NSCLC) patients with EGFR T790M mutation. However, resistance to OSI is 
likely to progress and the study of potential OSI-resistant mechanisms in 
advanced is necessary. Here, the OSI-resistant NCI-H1975/OSIR cells were 
established. After cells developed resistance to OSI, cell proliferation was 
decreased while cell migration and invasion were increased. The NCI-H1975/OSIR 
cells exhibited more resistance to gefitinib, erlotinib, afatinib, rociletinib, 
doxorubicin, and fluorouracil, meanwhile showing higher sensitivity to 
paclitaxel, when compared with NCI-H1975 cells. In addition, the NCI-H1975/OSIR 
cells did not display multidrug resistance phenotype. The activation and 
expression of EGFR were decreased after cells exhibited resistance. Compared 
with NCI-H1975 cells, the activation of ERK and AKT in NCI-H1975/OSIR cells 
could not be significantly inhibited by OSI treatment. Navitoclax 
(ABT-263)-induced cell viability inhibition and apoptosis were more significant 
in NCI-H1975/OSIR cells than that in NCI-H1975 cells. Moreover, these effects of 
navitoclax in NCI-H1975/OSIR cells could be reversed by pretreatment of 
Z-VAD-FMK. Collectively, loss of EGFR could pose as one of the OSI-resistant 
mechanisms and navitoclax might be the candidate drug for OSI-resistant NSCLC 
patients.