Objective To establish a crizotinib-resistant line of the EML4-ALK-positive lung adenocarcinoma cell line H2228 and compare it with the crizotinib-sensitive parental line to examine the possible role of BIM in crizotinib-induced apoptosis.

Methods H2228 human lung cells were exposed to gradually increasing doses of crizotinib（50，100，200，500，1000 nmol/L）to create a crizotinib-resistant line（H2228/CR）. Then H2228/CR and parental H2228 cells were exposed to different doses of crizotinib，and their growth was compared using the MTT assay，while levels of apoptosis were compared using flow cytometry. Western blotting was used to compare levels of ALK，p-ALK，ERK，p-ERK and BIM in the two cell lines.

Results After 8 months of crizotinib selection，the resistant line H2228/CR showed an IC50 of 3，418 nmol/L compared to 335 nmol/L for the parental H2228 line. The RI for H2228/CR cells was 10.20. Crizotinib inhibited the growth of H2228/CR cells to a much smaller extent than it inhibited H2228， and it led to a much smaller proportion of apoptotic cells in H2228/CR cultures. Levels of phospho-ERK were higher in H2228/CR cells， implying down-regulation of BIM.

Conclusion BIM may help mediate crizotinib-induced apoptosis in lung cancer， and its down-regulation may contribute to crizotinib resistance.