title: 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: Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan. Electronic address: ryohei.katayama@jfcr.or.jp.
authors: Ryohei
authors: R
authors: Katayama
authors: Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan; Department of Medical Genome Science, Graduate School of Frontier Science, The University of Tokyo, Tokyo 108-8639, Japan.
authors: Takuya
authors: T
authors: Sakashita
authors: Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan.
authors: Noriko
authors: N
authors: Yanagitani
authors: The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan.
authors: Hironori
authors: H
authors: Ninomiya
authors: Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan.
authors: Atsushi
authors: A
authors: Horiike
authors: Cancer Center, Massachusetts General Hospital, Charlestown, MA 02129, USA.
authors: Luc
authors: L
authors: Friboulet
authors: Cancer Center, Massachusetts General Hospital, Charlestown, MA 02129, USA.
authors: Justin F
authors: JF
authors: Gainor
authors: The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan.
authors: Noriko
authors: N
authors: Motoi
authors: The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan.
authors: Akito
authors: A
authors: Dobashi
authors: The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan.
authors: Seiji
authors: S
authors: Sakata
authors: Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan.
authors: Yuichi
authors: Y
authors: Tambo
authors: Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan.
authors: Satoru
authors: S
authors: Kitazono
authors: Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan.
authors: Shigeo
authors: S
authors: Sato
authors: Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan.
authors: Sumie
authors: S
authors: Koike
authors: Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA.
authors: A
authors: A
authors: John Iafrate
authors: Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA.
authors: Mari
authors: M
authors: Mino-Kenudson
authors: The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan.
authors: Yuichi
authors: Y
authors: Ishikawa
authors: Cancer Center, Massachusetts General Hospital, Charlestown, MA 02129, USA.
authors: Alice T
authors: AT
authors: Shaw
authors: Cancer Center, Massachusetts General Hospital, Charlestown, MA 02129, USA.
authors: Jeffrey A
authors: JA
authors: Engelman
authors: The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan.
authors: Kengo
authors: K
authors: Takeuchi
authors: Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan. Electronic address: mnishio@jfcr.or.jp.
authors: Makoto
authors: M
authors: Nishio
authors: Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan. Electronic address: naoya.fujita@jfcr.or.jp.
authors: Naoya
authors: N
authors: Fujita
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D008175:Lung Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D013902:Radiography, Thoracic; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D014057:Tomography, X-Ray Computed; D014178:Translocation, Genetic; D023041:Xenograft Model Antitumor Assays
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases
keywords: (sh)RNA, small hairpin; ABC, adenosine triphosphate (ATP)-binding cassette; ALK; ALK, anaplastic lymphoma kinase; ATP, adenosine triphosphate; BAC, bronchioloalveolar carcinoma; BBB, blood–brain 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