Genome-Wide Identification and Characterization of Novel Factors Conferring Resistance to Topoisomerase II Poisons in Cancer

• Published in: Cancer research (Chicago, Ill.) Ill.), 2015-10, Vol.75 (19), p.4176-4187
• Main Authors: Wijdeven, Ruud H, Pang, Baoxu, van der Zanden, Sabina Y, Qiao, Xiaohang, Blomen, Vincent, Hoogstraat, Marlous, Lips, Esther H, Janssen, Lennert, Wessels, Lodewyk, Brummelkamp, Thijn R, Neefjes, Jacques
• Format: Article
• Language: English
• Subjects: Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - physiology; Capecitabine - administration & dosage; Carcinoma - drug therapy; Carcinoma - genetics; Carcinoma - metabolism; Chromosomal Proteins, Non-Histone - genetics; Chromosomal Proteins, Non-Histone - physiology; CRISPR-Cas Systems; Cyclophosphamide - administration & dosage; DNA Helicases - analysis; DNA-Binding Proteins - genetics; DNA-Binding Proteins - physiology; Docetaxel; Doxorubicin - administration & dosage; Doxorubicin - pharmacology; Drug Resistance, Neoplasm - genetics; Etoposide - pharmacology; Female; Gene Expression Profiling; Genome-Wide Association Study; Humans; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - physiology; Kelch-Like ECH-Associated Protein 1; Neoplasm Proteins - analysis; Neoplasm Proteins - antagonists & inhibitors; Nuclear Proteins - analysis; Nuclear Proteins - genetics; Nuclear Proteins - physiology; RNA Interference; RNA, Small Interfering - pharmacology; Sarcoma - metabolism; Sarcoma - pathology; SMARCB1 Protein; Taxoids - administration & dosage; Topoisomerase II Inhibitors - pharmacology; Topotecan - pharmacology; Transcription Factors - analysis; Transcription Factors - genetics; Transcription Factors - physiology; Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - metabolism
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-15-0380

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.