کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2120866 1546896 2016 13 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
P-glycoprotein Mediates Ceritinib Resistance in Anaplastic Lymphoma Kinase-rearranged Non-small Cell Lung Cancer
موضوعات مرتبط
علوم زیستی و بیوفناوری بیوشیمی، ژنتیک و زیست شناسی مولکولی تحقیقات سرطان
پیش نمایش صفحه اول مقاله
P-glycoprotein Mediates Ceritinib Resistance in Anaplastic Lymphoma Kinase-rearranged Non-small Cell Lung Cancer
چکیده انگلیسی


• 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.

The anaplastic lymphoma kinase (ALK) fusion oncogene is observed in 3%–5% of non-small cell lung cancer (NSCLC). Crizotinib and ceritinib, a next-generation ALK tyrosine kinase inhibitor (TKI) active against crizotinib-refractory patients, are clinically available for the treatment of ALK-rearranged NSCLC patients, and multiple next-generation ALK-TKIs are currently under clinical evaluation. These ALK-TKIs exhibit robust clinical activity in ALK-rearranged NSCLC patients; however, the emergence of ALK-TKI resistance restricts the therapeutic effect. To date, various secondary mutations or bypass pathway activation-mediated resistance have been identified, but large parts of the resistance mechanism are yet to be identified. Here, we report the discovery of p-glycoprotein (P-gp/ABCB1) overexpression as a ceritinib resistance mechanism in ALK-rearranged NSCLC patients. P-gp exported ceritinib and its overexpression conferred ceritinib and crizotinib resistance, but not to PF-06463922 or alectinib, which are next-generation ALK inhibitors. Knockdown of ABCB1 or P-gp inhibitors sensitizes the patient-derived cancer cells to ceritinib, in vitro and in vivo. P-gp overexpression was identified in three out of 11 cases with in ALK-rearranged crizotinib or ceritinib resistant NSCLC patients. Our study suggests that alectinib, PF-06463922, or P-gp inhibitor with ceritinib could overcome the ceritinib or crizotinib resistance mediated by P-gp overexpression.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: EBioMedicine - Volume 3, January 2016, Pages 54–66
نویسندگان
, , , , , , , , , , , , , , ,