Ceritinib resistant patient-derived cancer cells overexpress P-gp without having mutation in ALK and other major oncogenes.

P-gp overexpression conferred the resistance to ceritinib and crizotinib but not to alectinib and PF-06463922.

Ceritinib is a substrate of P-gp, and P-gp-inhibitors or knockdown of P-gp reversed ceritinib resistance.

P-gp overexpression was observed in 3 out of 11 crizotinib- or ceritinib-resistant ALK-rearranged NSCLC patients.

For treatment of ALK-rearranged NSCLC, two ALK-TKIs, crizotinib and ceritinib are currently in use, but the emergence of acquired resistance limits the efficacy of ALK-TKIs. Except for the resistance-associated mutations in ALK, ALK-TKIs resistance mechanisms are still largely unknown. Here we identified P-gp overexpression mediating resistance in three ceritinib-resistant ALK-rearranged NSCLC patients. P-gp overexpression conferred ceritinib and crizotinib resistance but did not confer alectinib and PF-06463922 resistance, and treatment using P-gp inhibitor with ceritinib, or alectinib- or PF-06463922- monotherapy overcame the resistance, suggesting that P-gp expression could be an important determinant in the future treatment strategies.