Cancer cells that harbor inactivating p53 mutations exhibit checkpoint defects and impaired DNA damage responses. Because p53 mutations are prevalent in many common cancers, strategies that would exploit these defects are predicted to have significant clinical impact. This proposal is focused on the ATR pathway, which has recently emerged as a critical modulator of p53-deficient cancer cell survival in response to therapeutic agents. The ATR kinase holoenzyme is activated by DNA damage and DNA replication stress, and is therefore responsive to many of the anticancer agents currently in use. Recent studies have revealed new mechanisms by which ATR is controlled. These insights provide new opportunities to target this pathway. This proposed project employs genetic and biochemical methods to study the protein-protein interactions that define the competent ATR complex, and the effects of common chemotherapeutic agents on complex formation. The effectiveness of targeting distinct upstream and downstream components of the ATR pathway, including Cdk2 and Chk1, will be comparatively evaluated in vitro and in vivo. In a coordinated effort, a pharmacogenetic array of approved drugs will be screened to identify new ATR activators. Human somatic cells with targeted genetic alterations will be used to identify new drug/target combinations. A focused effort will be made to screen for genes that promote survival in response to cisplatin, an anticancer drug recently found to induce distinct survival pathways in cells that are deficient for p53. The long-term objectives of this project are to reveal basic mechanisms of ATR regulation, new drug targets, and new strategies for generating synthetic lethality in p53-deficient human cancer cells.
A significant proportion of all human cancers acquire mutations in the p53 gene that cause tumor cells to respond abnormally to the DNA damaging agents, such as ionizing radiation that are commonly used in the clinic. This project exploits new insights into DNA damage signaling to evaluate new strategies and drug targets designed to preferentially sensitize p53-mutant cancers, and thereby render them more responsive to existing modes of therapy.
|Miciak, Jessica; Bunz, Fred (2017) Understanding the pluses of pulses. Cell Cycle 16:1325|
|Illuzzi, Jennifer L; McNeill, Daniel R; Bastian, Paul et al. (2017) Tumor-associated APE1 variant exhibits reduced complementation efficiency but does not promote cancer cell phenotypes. Environ Mol Mutagen 58:84-98|
|Miciak, Jessica; Bunz, Fred (2016) Long story short: p53 mediates innate immunity. Biochim Biophys Acta 1865:220-7|
|Ivkov, Robert; Bunz, Fred (2015) Pathways to chromothripsis. Cell Cycle 14:2886-90|
|Larsen, Andrew R; Bai, Ren-Yuan; Chung, Jon H et al. (2015) Repurposing the antihelmintic mebendazole as a hedgehog inhibitor. Mol Cancer Ther 14:3-13|
|Bai, Ren-Yuan; Staedtke, Verena; Rudin, Charles M et al. (2015) Effective treatment of diverse medulloblastoma models with mebendazole and its impact on tumor angiogenesis. Neuro Oncol 17:545-54|
|Chung, Jon H; Larsen, Andrew R; Chen, Evan et al. (2014) A PTCH1 homolog transcriptionally activated by p53 suppresses Hedgehog signaling. J Biol Chem 289:33020-31|
|Li, Jie; Ma, Wenzhe; Wang, Ping-yuan et al. (2014) Polo-like kinase 2 activates an antioxidant pathway to promote the survival of cells with mitochondrial dysfunction. Free Radic Biol Med 73:270-7|
|Cui, Ying; Hausheer, Frederick; Beaty, Robert et al. (2014) A recombinant reporter system for monitoring reactivation of an endogenously DNA hypermethylated gene. Cancer Res 74:3834-43|
|Chung, Jon H; Bunz, Fred (2013) A loss-of-function mutation in PTCH1 suggests a role for autocrine hedgehog signaling in colorectal tumorigenesis. Oncotarget 4:2208-11|
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