Resistance to Pyrrolobenzodiazepine Dimers Is Associated with SLFN11 Downregulation and Can Be Reversed through Inhibition of ATR
| Autor: | Luke A. Masterson, Sonja Hess, Howard Philip Wilson, Andrew Garcia, Kimberly M Cook, Kathryn M. Pugh, Wen Yu, Hong Chen, Allison M. Barrett, Ronald Herbst, Shenlan Mao, Changshou Gao, David A. Tice, Mark Cobbold, Herren Wu, Jens-Oliver Koopmann, Ryan Fleming, Jay Harper, Susan Wilson, Raghothama Chaerkady, Gina DAngelo, Sandrina Phipps, Nazzareno Dimasi |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research Pyrrolobenzodiazepine Down-Regulation Ataxia Telangiectasia Mutated Proteins Transfection behavioral disciplines and activities 03 medical and health sciences chemistry.chemical_compound Benzodiazepines 0302 clinical medicine Downregulation and upregulation Histone methylation medicine Humans Pyrroles EZH2 Nuclear Proteins medicine.disease body regions 030104 developmental biology Oncology chemistry Cell culture Drug Resistance Neoplasm 030220 oncology & carcinogenesis Cancer cell Ataxia-telangiectasia Cancer research Female Schlafen family member 11 |
| Zdroj: | Molecular cancer therapeutics. 20(3) |
| ISSN: | 1538-8514 |
| Popis: | Resistance to antibody–drug conjugates (ADCs) has been observed in both preclinical models and clinical studies. However, mechanisms of resistance to pyrrolobenzodiazepine (PBD)-conjugated ADCs have not been well characterized and thus, this study was designed to investigate development of resistance to PBD dimer warheads and PBD-conjugated ADCs. We established a PBD-resistant cell line, 361-PBDr, by treating human breast cancer MDA-MB-361 cells with gradually increasing concentrations of SG3199, the PBD dimer released from the PBD drug-linker tesirine. 361-PBDr cells were over 20-fold less sensitive to SG3199 compared with parental cells and were cross-resistant to other PBD warhead and ADCs conjugated with PBDs. Proteomic profiling revealed that downregulation of Schlafen family member 11 (SLFN11), a putative DNA/RNA helicase, sensitizing cancer cells to DNA-damaging agents, was associated with PBD resistance. Confirmatory studies demonstrated that siRNA knockdown of SLFN11 in multiple tumor cell lines conferred reduced sensitivity to SG3199 and PBD-conjugated ADCs. Treatment with EPZ011989, an EZH2 inhibitor, derepressed SLFN11 expression in 361-PBDr and other SLFN11-deficient tumor cells, and increased sensitivity to PBD and PBD-conjugated ADCs, indicating that the suppression of SLFN11 expression is associated with histone methylation as reported. Moreover, we demonstrated that combining an ataxia telangiectasia and Rad3-related protein (ATR) inhibitor, AZD6738, with SG3199 or PBD-based ADCs led to synergistic cytotoxicity in either resistant 361-PBDr cells or cells that SLFN11 was knocked down via siRNA. Collectively, these data provide insights into potential development of resistance to PBDs and PBD-conjugated ADCs, and more importantly, inform strategy development to overcome such resistance. |
| Databáze: | OpenAIRE |
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