title: Targeting Adenine Nucleotide Translocase-2 (ANT2) to Overcome Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor in Non-Small Cell Lung Cancer.
abstract: EGFR tyrosine kinase inhibitor (EGFR-TKI) therapy has achieved favorable clinical outcomes in non-small cell lung cancer (NSCLC) patients with EGFR mutations. However, patients eventually develop resistance to EGFR-TKIs by several mechanisms. Adenine nucleotide translocase-2 (ANT2) is an oncogenic mitochondrial membrane-associated protein. We investigated the therapeutic potential of ANT2 inhibition to EGFR-TKI resistance in NSCLC using gefitinib-sensitive (PC9 and HCC827) and gefitinib-resistant (H1975 and HCC827/GR) NSCLC cell lines. ANT2 was inhibited by transfecting cells with an ANT2-specific shRNA. ANT2 expression was elevated in the H1975 and HCC827/GR cells compared with the PC9 and HCC827 cells. ANT2 upregulation in gefitinib-resistant cells was associated with increased SP1 binding to the ANT2 promoter. ANT2-specific shRNA decreased NSCLC cell viability. Moreover, ANT2-specific shRNA sensitized the H1975 and HCC827/GR cells to gefitinib, accompanied by HSP90 and EGFR downregulation. ANT2-specific shRNA also inactivated the PI3K/Akt signaling pathway in the H1975 and HCC827/GR cells, which was mediated by the suppression of miR-221/222 levels and by the subsequent restoration of PTEN. In EGFR-TKI-treated NSCLC patients, ANT2 expression was higher in patients exhibiting poor responses compared with patients showing excellent responses. Furthermore, ANT2 expression increased in tumor tissues biopsied after acquiring gefitinib resistance compared with tissues before gefitinib treatment. These findings suggest that ANT2 overexpression contributes to EGFR-TKI resistance in NSCLC and that ANT2 targeting may be considered a novel strategy for overcoming this resistance. Mol Cancer Ther; 15(6); 1387-96. ©2016 AACR.
authors.affiliation: Tumor Immunity Medical Research Center, Cancer Research Center, Seoul National University College of Medicine, Seoul, South Korea. Tumor Microenvironment Global Core Research Center, Seoul National University, Seoul, South Korea.
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Jang
authors.affiliation: Tumor Immunity Medical Research Center, Cancer Research Center, Seoul National University College of Medicine, Seoul, South Korea. Tumor Microenvironment Global Core Research Center, Seoul National University, Seoul, South Korea.
authors.forename: Yong-Goo
authors.initials: YG
authors.lastname: Kim
authors.affiliation: Tumor Immunity Medical Research Center, Cancer Research Center, Seoul National University College of Medicine, Seoul, South Korea. Tumor Microenvironment Global Core Research Center, Seoul National University, Seoul, South Korea. Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Soo Jeong
authors.initials: SJ
authors.lastname: Nam
authors.affiliation: Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Bhumsuk
authors.initials: B
authors.lastname: Keam
authors.affiliation: Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Tae Min
authors.initials: TM
authors.lastname: Kim
authors.affiliation: Tumor Immunity Medical Research Center, Cancer Research Center, Seoul National University College of Medicine, Seoul, South Korea. Tumor Microenvironment Global Core Research Center, Seoul National University, Seoul, South Korea. Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Yoon Kyung
authors.initials: YK
authors.lastname: Jeon
authors.affiliation: Tumor Immunity Medical Research Center, Cancer Research Center, Seoul National University College of Medicine, Seoul, South Korea. Tumor Microenvironment Global Core Research Center, Seoul National University, Seoul, South Korea. Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea. cwkim@snu.ac.kr.
authors.forename: Chul Woo
authors.initials: CW
authors.lastname: Kim
mesh_terms: D033742:Adenine Nucleotide Translocator 2 / Q000037:antagonists & inhibitors / Q000235:genetics*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D066246:ErbB Receptors / Q000378:metabolism; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D058990:Molecular Targeted Therapy; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011799:Quinazolines / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D033742:Adenine Nucleotide Translocator 2; D000970:Antineoplastic Agents; D011799:Quinazolines; D034741:RNA, Small Interfering; C512478:EGFR protein, human; D066246:ErbB Receptors; D000077156:Gefitinib