title: Osimertinib (AZD9291) Enhanced the Efficacy of Chemotherapeutic Agents in ABCB1- and ABCG2-Overexpressing Cells In Vitro, In Vivo, and Ex Vivo.
abstract: The overexpression of ATP-binding cassette (ABC) transporters has been proved to be a major trigger for multidrug resistance (MDR) in certain types of cancer. In our study, we investigated whether osimertinib (AZD9291), a third-generation irreversible tyrosine kinase inhibitor of both activating EGFR mutations and resistance-associated T790M point mutation, could reverse MDR induced by ABCB1 and ABCG2 in vitro, in vivo, and ex vivo Our results showed that osimertinib significantly increased the sensitivity of ABCB1- and ABCG2-overexpressing cells to their substrate chemotherapeutic agents in vitro and in the model of ABCB1-overexpressing KBv200 cell xenograft in nude mice. Mechanistically, osimertinib increased the intracellular accumulations of doxorubicin (DOX) and Rhodamine 123 (Rho 123) by inhibiting the efflux function of the transporters in ABCB1- or ABCG2-overexpressing cells but not in their parental sensitive cells. Furthermore, osimertinib stimulated the ATPase activity of both ABCB1 and ABCG2 and competed with the [(125)I] iodoarylazidoprazosin photolabeling bound to ABCB1 or ABCG2, but did not alter the localization and expression of ABCB1 or ABCG2 in mRNA and protein levels nor the phosphorylations of EGFR, AKT, and ERK. Importantly, osimertinib also enhanced the cytotoxicity of DOX and intracellular accumulation of Rho 123 in ABCB1-overexpressing primary leukemia cells. Overall, these findings suggest osimertinib reverses ABCB1- and ABCG2-mediated MDR via inhibiting ABCB1 and ABCG2 from pumping out chemotherapeutic agents and provide possibility for cancer combinational therapy with osimertinib in the clinic. Mol Cancer Ther; 15(8); 1845-58. ©2016 AACR.
authors.affiliation: Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China. Guangdong Esophageal Cancer Institute, Guangzhou, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China.
authors.forename: Yifan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Xu
authors.affiliation: Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China.
authors.forename: Likun
authors.initials: L
authors.lastname: Chen
authors.affiliation: Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Zhang
authors.affiliation: School of Pharmacy, the Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Kenneth Kin Wah
authors.initials: KK
authors.lastname: To
authors.affiliation: Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China.
authors.forename: Hongyun
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China. Guangdong Esophageal Cancer Institute, Guangzhou, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.affiliation: Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China.
authors.forename: Zhongjun
authors.initials: Z
authors.lastname: Xia
authors.affiliation: Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China.
authors.forename: Xiaoqin
authors.initials: X
authors.lastname: Chen
authors.affiliation: Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China. Guangdong Esophageal Cancer Institute, Guangzhou, China. Fulw@mail.sysu.edu.cn.
authors.forename: Liwu
authors.initials: L
authors.lastname: Fu
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000235:genetics* / Q000378:metabolism; D000178:Acrylamides; D000814:Aniline Compounds; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004357:Drug Synergism; D066246:ErbB Receptors / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression; D006801:Humans; D051379:Mice; D017239:Paclitaxel / Q000494:pharmacology; D010766:Phosphorylation; D010879:Piperazines; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D007211:Indoles; D011743:Pyrimidines
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D000178:Acrylamides; D000814:Aniline Compounds; D000970:Antineoplastic Agents; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D017239:Paclitaxel; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; C000596361:osimertinib; D007211:Indoles; D011743:Pyrimidines