ヒグチ　ケイ   Higuchi Kei   樋口　慧    所属   東邦大学  薬学部 薬学科    職種   准教授
論文種別	原著
言語種別	英語
査読の有無	査読あり
表題	SLC46A3 is a lysosomal proton-coupled steroid conjugate and bile acid transporter involved in transport of active catabolites of T-DM1
掲載誌名	正式名：PNAS Nexus ISSNコード：/2752-6542
出版社	Oxford University Press (OUP)
巻・号・頁	1(3)
著者・共著者	Ryuto Tomabechi,Hisanao Kishimoto,Taeka Sato,Naoki Saito,Keisuke Kiyomiya,Tappei Takada,Kei Higuchi,Yoshiyuki Shirasaka,Katsuhisa Inoue
発行年月	2022/07/19
概要	Abstract Antibody–drug conjugates (ADCs) represent a new class of cancer therapeutics that enable targeted delivery of cytotoxic drugs to cancer cells. Although clinical efficacy has been demonstrated for ADC therapies, resistance to these conjugates may occur. Recently, SLC46A3, a lysosomal membrane protein, was revealed to regulate the efficacy of trastuzumab emtansine (T-DM1), a noncleavable ADC that has been widely used for treating breast cancer. However, the role of SLC46A3 in mediating T-DM1 cytotoxicity remains unclear. In this study, we discovered the function of SLC46A3 as a novel proton-coupled steroid conjugate and bile acid transporter. SLC46A3 preferentially recognized lipophilic steroid conjugates and bile acids as endogenous substrates. In addition, we found that SLC46A3 directly transports Lys-SMCC-DM1, a major catabolite of T-DM1, and potent SLC46A3 inhibitors attenuate the cytotoxic effects of T-DM1, suggesting a role in the escape of Lys-SMCC-DM1 from the lysosome into the cytoplasm. Our findings reveal the molecular mechanism by which T-DM1 kills cancer cells and may contribute to the rational development of ADCs that target SLC46A3.
DOI	10.1093/pnasnexus/pgac063
PermalinkURL	https://academic.oup.com/pnasnexus/advance-article-pdf/doi/10.1093/pnasnexus/pgac063/43777626/pgac063.pdf
researchmap用URL	https://academic.oup.com/pnasnexus/article-pdf/1/3/pgac063/45025537/pgac063.pdf