title: ABCB5-Targeted Chemoresistance Reversal Inhibits Merkel Cell Carcinoma Growth.
abstract: Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine skin cancer with profound but poorly understood resistance to chemotherapy, which poses a significant barrier to clinical MCC treatment. Here we show that ATP-binding cassette member B5 (ABCB5) confers resistance to standard-of-care MCC chemotherapeutic agents and provide proof-of-principle that ABCB5 blockade can inhibit human MCC tumor growth through sensitization to drug-induced cell cytotoxicity. ABCB5 expression was detected in both established MCC lines and clinical MCC specimens at levels significantly higher than those in normal skin. Carboplatin- and etoposide-resistant MCC cell lines exhibited increased expression of ABCB5, along with enhanced ABCB1 and ABCC3 transcript expression. ABCB5-expressing MCC cells in heterogeneous cancers preferentially survived treatment with carboplatin and etoposide in vitro and in human MCC xenograft-bearing mice in vivo. Moreover, patients with MCC also exhibited enhanced ABCB5 positivity after carboplatin- and etoposide-based chemotherapy, pointing to clinical significance of this chemoresistance mechanism. Importantly, ABCB5 blockade reversed MCC drug resistance and impaired tumor growth in xenotransplantation models in vivo. Our results establish ABCB5 as a chemoresistance mechanism in MCC and suggest utility of this molecular target for improved MCC therapy.
authors.affiliation: Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Sonja
authors.initials: S
authors.lastname: Kleffel
authors.affiliation: Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Nayoung
authors.initials: N
authors.lastname: Lee
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Lezcano
authors.affiliation: Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Wilson
authors.affiliation: Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Kristine
authors.initials: K
authors.lastname: Sobolewski
authors.affiliation: Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Karim R
authors.initials: KR
authors.lastname: Saab
authors.affiliation: Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Hansgeorg
authors.initials: H
authors.lastname: Mueller
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhan
authors.affiliation: Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Posch
authors.affiliation: Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Elco
authors.affiliation: Dana Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: DoRosario
authors.affiliation: Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Dana Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Sarah S
authors.initials: SS
authors.lastname: Garcia
authors.affiliation: Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Dana Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Manisha
authors.initials: M
authors.lastname: Thakuria
authors.affiliation: Center for Cancer Computational Biology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Yaoyu E
authors.initials: YE
authors.lastname: Wang
authors.affiliation: Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Dana Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Linda C
authors.initials: LC
authors.lastname: Wang
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: George F
authors.initials: GF
authors.lastname: Murphy
authors.affiliation: Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA; School of Medical Sciences, Edith Cowan University, Joondalup, WA, Australia. Electronic address: markus.frank@childrens.harvard.edu.
authors.forename: Markus H
authors.initials: MH
authors.lastname: Frank
authors.affiliation: Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA. Electronic address: tschatton@bwh.harvard.edu.
authors.forename: Tobias
authors.initials: T
authors.lastname: Schatton
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D016190:Carboplatin / Q000008:administration & dosage; D015266:Carcinoma, Merkel Cell / Q000188:drug therapy / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000008:administration & dosage; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D053631:Interleukin Receptor Common gamma Subunit / Q000235:genetics; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D009368:Neoplasm Transplantation; D060888:Real-Time Polymerase Chain Reaction; D012867:Skin / Q000378:metabolism; D012878:Skin Neoplasms / Q000188:drug therapy / Q000378:metabolism*
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D016190:Carboplatin; D005047:Etoposide; D053631:Interleukin Receptor Common gamma Subunit; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C513055:ABCB1 protein, human; C480744:ABCB5 protein, human; C507941:IL2RG protein, human; C114462:multidrug resistance-associated protein 3
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