Temozolomide Sensitizes MGMT-Deficient Tumor Cells to ATR Inhibitors
Autor: | Ranjini K. Sundaram, Jann N. Sarkaria, Seth Noorbakhsh, Christopher Jackson, Danielle M. Burgenske, Ranjit S. Bindra, Aravind N. Kalathil, Sachita Ganesa, Oren Gilad, Lanqi Jia, Hank J. Breslin |
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Rok vydání: | 2019 |
Předmět: |
0301 basic medicine
Cancer Research Methyltransferase DNA damage Mice Nude Ataxia Telangiectasia Mutated Proteins Article 03 medical and health sciences 0302 clinical medicine Therapeutic index Cell Line Tumor Glioma Antineoplastic Combined Chemotherapy Protocols Temozolomide medicine Animals Humans DNA Breaks Double-Stranded Antineoplastic Agents Alkylating DNA Modification Methylases neoplasms Kinase Chemistry Tumor Suppressor Proteins Drug Synergism Cell Cycle Checkpoints Isoxazoles medicine.disease Xenograft Model Antitumor Assays digestive system diseases DNA Repair Enzymes 030104 developmental biology Oncology Cell culture Pyrazines 030220 oncology & carcinogenesis Checkpoint Kinase 1 Ataxia-telangiectasia Cancer research Female DNA Damage medicine.drug |
Zdroj: | Cancer Research. 79:4331-4338 |
ISSN: | 1538-7445 0008-5472 |
DOI: | 10.1158/0008-5472.can-18-3394 |
Popis: | O6-methylguanine-DNA methyltransferase (MGMT) is an enzyme that removes alkyl groups at the O6-position of guanine in DNA. MGMT expression is reduced or absent in many tumor types derived from a diverse range of tissues, most notably in glioma. Low MGMT expression confers significant sensitivity to DNA alkylating agents such as temozolomide, providing a natural therapeutic index over normal tissue. In this study, we sought to identify novel approaches that could maximally exploit the therapeutic index between tumor cells and normal tissues based on MGMT expression, as a means to enhance selective tumor cell killing. Temozolomide, unlike other alkylators, activated the ataxia telangiectasia and Rad3–related (ATR)–checkpoint kinase 1 (Chk1) axis in a manner that was highly dependent on MGMT status. Temozolomide induced growth delay, DNA double-strand breaks, and G2–M cell-cycle arrest, which led to ATR-dependent phosphorylation of Chk1; this effect was dependent on reduced MGMT expression. Treatment of MGMT-deficient cells with temozolomide increased sensitivity to ATR inhibitors both in vitro and in vivo across numerous tumor cell types. Taken together, this study reveals a novel approach for selectively targeting MGMT-deficient cells with ATR inhibitors and temozolomide. As ATR inhibitors are currently being tested in clinical trials, and temozolomide is a commonly used chemotherapeutic, this approach is clinically actionable. Furthermore, this interaction potently exploits a DNA-repair defect found in many cancers. Significance: Monofunctional alkylating agents sensitize MGMT-deficient tumor cells to ATR inhibitors. |
Databáze: | OpenAIRE |
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