Therapeutic Discovery Targeted Mutations in the ATR Pathway Define Agent- Specific Requirements for Cancer Cell Growth and Survival
نویسندگان
چکیده
Many anticancer agents induce DNA strand breaks or cause the accumulation of DNA replication intermediates. The protein encoded by ataxia-telangiectasia mutated and Rad 3-related (ATR) generates signals in response to these altered DNA structures and activates cellular survival responses. Accordingly, ATR has drawn increased attention as apotential target for novel therapeutic strategies designed topotentiate the effects of existing drugs. In this study, we use a unique panel of genetically modified human cancer cells to unambiguously test the roles of upstream and downstream components of the ATR pathway in the responses to common therapeutic agents. Upstream, the S-phase–specific cyclin-dependent kinase (Cdk) 2 was required for robust activation of ATR in response to diverse chemotherapeutic agents. While Cdk2-mediated ATR activation promoted cell survival after treatment with many drugs, signaling from ATR directly to the checkpoint kinase Chk1 was required for survival responses to only a subset of the drugs tested. These results show that specifically inhibiting the Cdk2/ATR/Chk1 pathway via distinct regulators can differentially sensitize cancer cells to a wide range of therapeutic agents. Mol Cancer Ther; 11(1); 98–107. 2011 AACR.
منابع مشابه
Targeted mutations in the ATR pathway define agent-specific requirements for cancer cell growth and survival.
Many anticancer agents induce DNA strand breaks or cause the accumulation of DNA replication intermediates. The protein encoded by ataxia-telangiectasia mutated and Rad 3-related (ATR) generates signals in response to these altered DNA structures and activates cellular survival responses. Accordingly, ATR has drawn increased attention as a potential target for novel therapeutic strategies desig...
متن کاملNanomedicine – The role of newer drug delivery technologies in cancer
Nanotechnology has slowly but steadily revolutionized the diagnosis, imaging and treatment of cancer. Detecting cancer at earliest stages, locating the tumor at different areas in the body and specific delivery of the drugs to malignant cells including surgically inaccessible tumors are the core areas of medical and pharmaceutical research across the world. In this endeavour, Nanodevices have e...
متن کاملNanomedicine – The role of newer drug delivery technologies in cancer
Nanotechnology has slowly but steadily revolutionized the diagnosis, imaging and treatment of cancer. Detecting cancer at earliest stages, locating the tumor at different areas in the body and specific delivery of the drugs to malignant cells including surgically inaccessible tumors are the core areas of medical and pharmaceutical research across the world. In this endeavour, Nanodevices have e...
متن کاملEffects of Dendritic Cell Vaccine Activated with Components of Lieshmania Major on Tumor Specific Response
Background: Dendritic cells (DCs) contribute essentially to the outset and course of immune responses. So in patients with malignancy, there have been considerable interests in use of these cells in different interventions. Objective: To evaluate the impact of Leishmania major’s components on DC maturation and their use as a therapeutic agent against t...
متن کاملEvaluation of antioxidant and anti-cancer properties of curcumin / beta- and gamma-cyclodextrin complexes modified with chitosan nanoparticles on lung cancer cell A549
The aim of this study was to investigate the interaction modification of curcumin complex molecule (CUR) in beta- and gamma-cyclodextrin (β-CD and γ-CD) carriers with chitosan (CS) nanoparticles for targeted drug delivery and to compare their performance. The targeted drug delivery system includes the therapeutic agent of the CS nanoparticles targeting section of the same drug and the CD carrie...
متن کامل