P-glycoprotein Mediates Ceritinib Resistance in Anaplastic Lymphoma Kinase-rearranged Non-small Cell Lung Cancer.
EBioMedicine
; 3: 54-66, 2016 Jan.
Article
en En
| MEDLINE
| ID: mdl-26870817
ABSTRACT
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.
Palabras clave
(sh)RNA, small hairpin; ABC, adenosine triphosphate (ATP)-binding cassette; ALK; ALK, anaplastic lymphoma kinase; ATP, adenosine triphosphate; BAC, bronchioloalveolar carcinoma; BBB, bloodbrain barrier; BCRP, breast cancer resistance protein; CAF, cyclophosphamide, doxorubicin, and fluorouracil; CSCs, cancer stem/initiating cells; CT, computed tomography; Ceritinib; Crizotinib; EGFR, epidermal growth factor receptor; FBS, fetal bovine serum; FISH, fluorescence in situ hybridization; IC50, half-maximal inhibitory concentration; IHC, immunohistochemical; IRB, institutional review board; K562/VCR, K562-derived vincristine-resistant; LCNEC, large cell neuroendocrine carcinoma; MRP1, multidrug Resistance-associated Protein 1; ORR, overall response rate; OS, overall survival; P-glycoprotein; P-gp, P-glycoprotein; PFS, progression-free survival; ROS1, v-ros avian ur2 sarcoma virus oncogene homolog 1; RPMI, Roswell Park Memorial Institute; Resistance; SP, side population; TKI, tyrosine kinase inhibitor; TNM, tumor-node-metastasis; Tyrosine kinase
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Translocación Genética
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Proteínas Tirosina Quinasas Receptoras
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Carcinoma de Pulmón de Células no Pequeñas
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Miembro 1 de la Subfamilia B de Casetes de Unión a ATP
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Resistencia a Antineoplásicos
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Neoplasias Pulmonares
Tipo de estudio:
Diagnostic_studies
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Prognostic_studies
Límite:
Animals
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Female
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Humans
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Middle aged
Idioma:
En
Revista:
EBioMedicine
Año:
2016
Tipo del documento:
Article