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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA157535-02
Application #
8300806
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Arya, Suresh
Project Start
2011-07-13
Project End
2016-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
2
Fiscal Year
2012
Total Cost
$340,300
Indirect Cost
$132,800
Name
Johns Hopkins University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Larsen, Andrew R; Bai, Ren-Yuan; Chung, Jon H et al. (2015) Repurposing the antihelmintic mebendazole as a hedgehog inhibitor. Mol Cancer Ther 14:13-Mar
Wilsker, Deborah; Chung, Jon H; Pradilla, Ivan et al. (2012) Targeted mutations in the ATR pathway define agent-specific requirements for cancer cell growth and survival. Mol Cancer Ther 11:98-107
Wilsker, Deborah; Chung, Jon H; Bunz, Fred (2012) Chk1 suppresses bypass of mitosis and tetraploidization in p53-deficient cancer cells. Cell Cycle 11:1564-72