P-glycoprotein Mediates Ceritinib Resistance in Anaplastic Lymphoma Kinase-rearranged Non-small Cell Lung Cancer.

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.

• Authors: Ryohei Katayama, Takuya Sakashita, Noriko Yanagitani, Hironori Ninomiya, Atsushi Horiike, Luc Friboulet, Justin F Gainor, Noriko Motoi, Akito Dobashi, Seiji Sakata, Yuichi Tambo, Satoru Kitazono, Shigeo Sato, Sumie Koike, A John Iafrate, Mari Mino-Kenudson, Yuichi Ishikawa, Alice T Shaw, Jeffrey A Engelman, Kengo Takeuchi, Makoto Nishio, Naoya Fujita
• Journal: EBioMedicine (EBioMedicine) Vol. 3 Pg. 54-66 (Jan 2016) ISSN: 2352-3964 [Electronic] Netherlands
• PMID: 26870817 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Antineoplastic Agents
• Protein Kinase Inhibitors
• ALK protein, human
• Anaplastic Lymphoma Kinase
• Receptor Protein-Tyrosine Kinases

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (antagonists & inhibitors, genetics, metabolism)
• Anaplastic Lymphoma Kinase
• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Carcinoma, Non-Small-Cell Lung (diagnosis, drug therapy, genetics, metabolism)
• Cell Line, Tumor
• Disease Models, Animal
• Drug Resistance, Neoplasm
• Female
• Gene Expression Regulation, Neoplastic
• Gene Knockdown Techniques
• Humans
• Lung Neoplasms (diagnosis, drug therapy, genetics, metabolism)
• Middle Aged
• Mutation
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Radiography, Thoracic
• Receptor Protein-Tyrosine Kinases (genetics, metabolism)
• Tomography, X-Ray Computed
• Translocation, Genetic
• Xenograft Model Antitumor Assays