title: Genome-Wide Identification and Characterization of Novel Factors Conferring Resistance to Topoisomerase II Poisons in Cancer.
abstract: The topoisomerase II poisons doxorubicin and etoposide constitute longstanding cornerstones of chemotherapy. Despite their extensive clinical use, many patients do not respond to these drugs. Using a genome-wide gene knockout approach, we identified Keap1, the SWI/SNF complex, and C9orf82 (CAAP1) as independent factors capable of driving drug resistance through diverse molecular mechanisms, all converging on the DNA double-strand break (DSB) and repair pathway. Loss of Keap1 or the SWI/SNF complex inhibits generation of DSB by attenuating expression and activity of topoisomerase IIα, respectively, whereas deletion of C9orf82 augments subsequent DSB repair. Their corresponding genes, frequently mutated or deleted in human tumors, may impact drug sensitivity, as exemplified by triple-negative breast cancer patients with diminished SWI/SNF core member expression who exhibit reduced responsiveness to chemotherapy regimens containing doxorubicin. Collectively, our work identifies genes that may predict the response of cancer patients to the broadly used topoisomerase II poisons and defines alternative pathways that could be therapeutically exploited in treatment-resistant patients.
authors.affiliation: Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Ruud H
authors.initials: RH
authors.lastname: Wijdeven
authors.affiliation: Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Baoxu
authors.initials: B
authors.lastname: Pang
authors.affiliation: Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Sabina Y
authors.initials: SY
authors.lastname: van der Zanden
authors.affiliation: Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Xiaohang
authors.initials: X
authors.lastname: Qiao
authors.affiliation: Division of Biochemistry, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Vincent
authors.initials: V
authors.lastname: Blomen
authors.affiliation: Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Marlous
authors.initials: M
authors.lastname: Hoogstraat
authors.affiliation: Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. Division of Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Esther H
authors.initials: EH
authors.lastname: Lips
authors.affiliation: Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Lennert
authors.initials: L
authors.lastname: Janssen
authors.affiliation: Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Lodewyk
authors.initials: L
authors.lastname: Wessels
authors.affiliation: Division of Biochemistry, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Thijn R
authors.initials: TR
authors.lastname: Brummelkamp
authors.affiliation: Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. j.neefjes@nki.nl.
authors.forename: Jacques
authors.initials: J
authors.lastname: Neefjes
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000502:physiology*; D064113:CRISPR-Cas Systems; D000069287:Capecitabine / Q000008:administration & dosage; D002277:Carcinoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000502:physiology*; D003520:Cyclophosphamide / Q000008:administration & dosage; D004265:DNA Helicases / Q000032:analysis; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D000077143:Docetaxel; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D020869:Gene Expression Profiling; D055106:Genome-Wide Association Study; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology*; D000072019:Kelch-Like ECH-Associated Protein 1; D009363:Neoplasm Proteins / Q000032:analysis / Q000037:antagonists & inhibitors*; D009687:Nuclear Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D000071796:SMARCB1 Protein; D012509:Sarcoma / Q000378:metabolism / Q000473:pathology; D043823:Taxoids / Q000008:administration & dosage; D059005:Topoisomerase II Inhibitors / Q000494:pharmacology*; D019772:Topotecan / Q000494:pharmacology; D014157:Transcription Factors / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C000604240:CAAP1 protein, human; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D000071796:SMARCB1 Protein; C513266:SMARCB1 protein, human; D043823:Taxoids; D059005:Topoisomerase II Inhibitors; D014157:Transcription Factors; D000077143:Docetaxel; D000069287:Capecitabine; D005047:Etoposide; D019772:Topotecan; D004317:Doxorubicin; D003520:Cyclophosphamide; C084108:SMARCA4 protein, human; D004265:DNA Helicases