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Acquired Resistance to Alectinib in ALK-Rearranged Lung Cancer Due

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Acquired Resistance to Alectinib in ALK-Rearranged Lung Cancer Due Published OnlineFirst March 26, 2020; DOI: 10.1158/1535-7163.MCT-19-0649 MOLECULAR CANCER THERAPEUTICS | CANCER BIOLOGY AND TRANSLATIONAL STUDIES Acquired Resistance to Alectinib in ALK-Rearranged Lung Cancer due to ABCC11/MRP8 Overexpression in a Clinically Paired Resistance Model Tomoko Funazo1, Takahiro Tsuji1, Hiroaki Ozasa1, Koh Furugaki2, Yasushi Yoshimura2, Tetsuya Oguri3, Hitomi Ajimizu1, Yuto Yasuda1, Takashi Nomizo1, Yuichi Sakamori1, Hironori Yoshida1, Young Hak Kim1, and Toyohiro Hirai1 ABSTRACT ◥ Alectinib is used as a first-line treatment for anaplastic lympho- to alectinib in vitro. ABCC11-overexpressing cells were estab- ma kinase (ALK)-rearranged non–small cell lung cancer (NSCLC). lished by transfection of an ABCC11 expression vector into Whereas other ALK inhibitors have been reported to be involved in H2228 cells, while control cells were established by transfecting resistance to ATP-binding cassette (ABC) transporters, no data are H2228 cells with an empty vector. ABCC11-overexpressing cells available regarding the association between resistance to alectinib exhibited decreased sensitivity to alectinib compared with that of and ABC-transporters. To investigate whether ABC-transporters control cells in vitro. Moreover, the tumor growth rate following contribute to alectinib resistance, ABC-transporter expression in alectinib treatment was higher in ABCC11-overexpressing cells alectinib-resistant cell lines derived from a patient with ALK- than that in control cells in vivo. In addition, the intracellular rearranged NSCLC and from H2228 lung cancer cells was evaluated alectinib concentration following exposure to 100 nmol/L alec- and compared with that in each parent cell type. ATP-binding tinib was significantly lower in the ABCC11-overexpressing cell cassette subfamily C member 11 (ABCC11) expression was signif- line compared with that in control cells. This is the first pre- icantly increased in alectinib-resistant cell lines compared with that clinical evidence showing that ABCC11 expression may be in alectinib-sensitive lines. ABCC11 inhibition increased sensitivity involved in acquired resistance to alectinib. Introduction expression of drug efflux pumps such as ATP-binding cassette (ABC) transporters (5). Previous studies showed that the presence of sec- In 2007, a novel driver oncogene, EML4–ALK fusion gene, in ondary mutations such as I1171T/N/S, V1180L, L1196M, and G1202R which the echinoderm microtubule-associated protein-like 4 in the kinase domain of ALK conferred resistance to alectinib (6, 7). (EML4) gene is fused to the anaplastic lymphoma kinase (ALK) Another major resistance mechanism involves bypass salvage signal- gene, was identified in patients with non–small cell lung cancer ing that maintains downstream signaling pathways to activate survival, (NSCLC;refs.1,2).Notably,thesecond-generation ALK inhibitor, antiapoptotic, and proliferation signals. In particular, activation of alectinib, showed superior efficacy in primary treatment of ALK- EGFR has reported to maintain survival signaling that induces alecti- positive NSCLC compared with that of crizotinib, a first-generation nib resistance, and we have reported that coactivation of c-Src and ALK inhibitor (3, 4). However, although alectinib is used as the MET functions as salvage signaling under alectinib exposure (8, 9). first-line treatment for ALK-positive NSCLC, approximately 30% of ABC-transporters transport various molecules and are involved in patients treated with alectinib become refractory within a year of multidrug resistance to anticancer agents. In particular, nine ABC- treatment owing to acquired resistance (4). transporters, that is, multidrug resistance protein 1/ABCB1 (ABCB1), Several mechanisms of resistance to molecular-targeted therapeutic multidrug resistance-associated protein 1 (MRP1)/ABCC1 (ABCC1), agents have been reported including: mutations of the drug target; MRP2/ABCC2 (ABCC2), MRP3/ABCC3 (ABCC3), MRP4/ABCC4 activation of bypass signaling pathways; dysregulation of apoptosis; (ABCC4), MRP5/ABCC5 (ABCC5), MRP7/ABCC10 (ABCC10), tumor microenvironment including the extracellular matrix, immune MRP8/ABCC11 (ABCC11), and breast cancer resistance protein/ and inflammatory cells, and blood vessels; and increased protein ABCG2 (ABCG2) have been reported to be associated with anticancer drug resistance (10, 11). Moreover, several tyrosine kinase inhibitors (TKI; e.g., imatinib, nilotinib, dasatinib, ponatinib, gefitinib, erlotinib, 1 Department of Respiratory Medicine, Kyoto University Graduate School lapatinib, vandetanib, sunitinib, and sorafenib) were recently reported 2 of Medicine, Kyoto, Japan. Department of Product Research, Kamakura as substrates for ABC-transporters including ABCB1, ABCC1, Research Laboratories, Chugai Pharmaceutical, Kanagawa, Japan. 3Department of Education and Research Center for Community Medicine, Nagoya City ABCG2, and ABCC10 (12). Notably, overexpression of ABCB1 was University Graduate School of Medical Sciences, Nagoya, Japan. shown to be involved in the resistance to crizotinib and ceritinib, which constitute other ALK-TKIs, but not to alectinib (13). In addition, it was Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/). demonstrated that alectinib is not a substrate for ABCB1 and ABCG2 (14, 15). Thus, unlike other TKIs, the association between Corresponding Author: Hiroaki Ozasa, Kyoto University, 54 Shogoin Kawahara- cho, Sakyo-ku, Kyoto 606-8507, Japan. Phone: 817-5751-3830; Fax: 817-5751- alectinib resistance and ABC-transporter expression is not fully 4643; E-mail: [email protected] understood. Therefore, the aim of this study was to determine the ABC-transporters that are associated with alectinib resistance in lung Mol Cancer Ther 2020;19:1320–7 cancer. doi: 10.1158/1535-7163.MCT-19-0649 We previously reported the establishment of a clinical paired Ó2020 American Association for Cancer Research. resistant model (CPRM) comprised of patient-derived ALK- AACRJournals.org | 1320 Downloaded from mct.aacrjournals.org on October 1, 2021. © 2020 American Association for Cancer Research. Published OnlineFirst March 26, 2020; DOI: 10.1158/1535-7163.MCT-19-0649 ABCC11/MRP8 may Confer Alectinib Resistance rearranged NSCLC cell lines from a treatment-na€ve and subsequently, Immunoblotting alectinib-refractory patient (9). In this study, we evaluated the expres- SDS-PAGE and immunoblotting were performed as described sion of the nine chemoresistance-associated ABC-transporters in these previously (16). Briefly, antibodies against ABCC11 and GAPDH cell lines, identifying that ABCC11 expression was significantly were purchased from Invitrogen. pALK (pY 1604) and secondary increased in alectinib-resistant cells compared with that in alecti- antibodies were purchased from Cell Signaling Technology. b-actin nib-sensitive cells. Therefore, in this study we investigated whether was purchased from Sigma-Aldrich (details are provided in Supple- increased ABCC11 expression may constitute a mechanism underly- mentary Table S1). Antibodies against ABCC11 (1:2,000), GAPDH (1: ing the acquired resistance to alectinib. 10,000), pALK (1:1,000), and b-actin (1: 10,000), and secondary (1: 2,000) antibodies were dissolved in 2.5% BSA/TBS with Tween 20. BSA was purchased from Nacalai Tesque. Quantification of protein bands Materials and Methods was performed using ImageJ software (https://imagej.nih.gov/ij/). Clinical information and procedures for obtaining informed consent Quantitative reverse transcription-PCR The study protocol was prepared in accordance with the Declaration Total RNA was extracted from cultured cells using the PureLink of Helsinki and approved by the Kyoto University Graduate School RNA Mini Kit (Thermo Fisher Scientific). Gene expression was and Faculty of Medicine Ethics Committee (Kyoto, Japan; certification evaluated by quantitative reverse transcription-PCR (qRT-PCR) using number: R0996). The patient provided written informed consent to 100 ng of total RNA, the TaqMan RNA-to-Ct 1-Step Kit (Applied participate in this study. Biosystems), and a primer pair. A list of the primers purchased from Thermo Fisher Scientific is shown in Supplementary Table S2. Reac- Establishment of patient-derived lung cancer cells tions were quantified using the 7300 Real-Time PCR System (Applied KTOR1 and KTOR1-RE (EML4-ALK variant 1 E13; A20) cells Biosystems). were established from a 29-year-old female patient with ALK- rearranged NSCLC, who regularly visited Kyoto University Hospital Transfection with siRNA (Kyoto, Japan). The method used to establish the patient-derived ABCC11 siRNA oligonucleotides were purchased from Thermo cells was described previously (9). Briefly, 200 mL of pleural Fisher Scientific (Stealth RNAi siRNA; Supplementary Table S3). A effusion was obtained from the patient with ALK-rearranged lung total of 3.0 Â 105 cells were transfected with siRNA oligonucleotides at cancer. Tumor cells were separated by centrifugation at 800 rpm for a final RNA concentration of 21 nmol/L using Lipofectamine RNAi- 5 minutes, and then cultured and maintained in alectinib-free MAX Transfection Reagent (Invitrogen). The reverse transfection RPMI1640 Medium (Nacalai Tesque) supplemented with 8% method was performed according to the manufacturer's protocol. heat-inactivated FBS (Sigma-Aldrich) and 1% penicillin/streptomy- RNA and total protein were extracted at 30 and 54 hours, respectively, cin (Gibco) at 37.0 Cin5%CO2. Information
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