title: Human ATP-Binding Cassette transporters ABCB1 and ABCG2 confer resistance to CUDC-101, a multi-acting inhibitor of histone deacetylase, epidermal growth factor receptor and human epidermal growth factor receptor 2.
abstract: CUDC-101 is the first small-molecule inhibitor designed to simultaneously inhibit epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2) and histone deacetylase (HDAC) in cancer cells. Recently, in its first in human phase I study, CUDC-101 showed promising single agent activity against advanced solid tumors and favorable pharmacodynamic profile. However, the risk of developing drug resistance to CUDC-101 can still present a significant therapeutic challenge to clinicians in the future. One of the most common mechanisms of developing multidrug resistance (MDR) in cancer is associated with the overexpression of ATP-binding cassette (ABC) drug transporters ABCB1 and ABCG2. Together, they are able to reduce the efficacy and modify the pharmacological properties of anti-cancer agents, including many small molecule tyrosine kinase inhibitors (TKIs). Here, we have investigated the impact of ABCB1 and ABCG2 on the efficacy of CUDC-101 in human cancer cells. We revealed that although CUDC-101 has potent antiproliferative and proapoptotic activities against most cancer cell lines, the overexpression of ABCB1 or ABCG2 in cancer cells significantly reduced the activity of CUDC-101 against HDAC, EGFR and HER2, as well as its cytotoxicity and proapoptotic activity. Moreover, we showed that CUDC-101 modulated the function of both transporters without affecting the protein expression of either ABCB1 or ABCG2. More importantly, our study provides support for the rationale of combining CUDC-101 with modulators of ABC drug transporters to improve drug efficacy and overcome multidrug resistance associated with the overexpression of ABCB1 and ABCG2.
authors.affiliation: Department of Physiology and Pharmacology; Graduate Institute of Biomedical Sciences; Molecular Medicine Research Center, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan. Electronic address: wuchung@mail.cgu.edu.tw.
authors.forename: Chung-Pu
authors.initials: CP
authors.lastname: Wu
authors.affiliation: Graduate Institute of Biomedical Sciences.
authors.forename: Sung-Han
authors.initials: SH
authors.lastname: Hsiao
authors.affiliation: Graduate Institute of Biomedical Sciences.
authors.forename: Ching-Ya
authors.initials: CY
authors.lastname: Su
authors.affiliation: Graduate Institute of Biomedical Sciences.
authors.forename: Shi-Yu
authors.initials: SY
authors.lastname: Luo
authors.affiliation: Department of Physiology and Pharmacology.
authors.forename: Yan-Qing
authors.initials: YQ
authors.lastname: Li
authors.affiliation: Molecular Medicine Research Center, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan.
authors.forename: Yang-Hui
authors.initials: YH
authors.lastname: Huang
authors.affiliation: Graduate Institute of Basic Medical Science; Department of Medical Research, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Chia-Hung
authors.initials: CH
authors.lastname: Hsieh
authors.affiliation: Center for Advanced Molecular Imaging and Translation, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan.
authors.forename: Chiun-Wei
authors.initials: CW
authors.lastname: Huang
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000502:physiology; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000502:physiology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D009363:Neoplasm Proteins / Q000502:physiology*; D011799:Quinazolines / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D066246:ErbB Receptors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D009363:Neoplasm Proteins; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C549566:7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide; C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; C508053:ERBB2 protein, human
keywords: CUDC-101; EGFR; HDAC; HER2; Multidrug resistance