Cellular responses to DNA damage: From mechanistic insights to new cancer therapies – Steve Jackson, University of Cambridge, UK

12:40-13:20

Room: Hall 1A

Cellular responses to DNA damage: from mechanistic insights to new cancer therapies Stephen P. Jackson. The Gurdon Institute and Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, https://www.stevejacksonlab.org At rest, each human cell sustains tens-of-thousands of DNA lesions per day. Furthermore, additional DNA damage can be induced by agents such as ionizing radiation, chemotherapeutic drugs and environmental chemicals. To combat such threats to genome stability, our cells have evolved elaborate ways to detect, signal the presence of and repair DNA damage. The importance of such processes is highlighted by inherited or acquired defects in them causing various human pathologies, including immune-deficiencies, neurodegenerative diseases, premature ageing and cancer. Much work in my laboratory aims to decipher mechanisms of DNA repair and also to determine how these mechanisms impact on, and are influenced by, myriad aspects of cellular physiology. In this talk, I will explain how cells respond to highly toxic DNA double-strand breaks. I will then briefly review how research by my group and others has contributed to development of the drug, olaparib/LynparzaTM, which inhibits the DNA-repair enzyme PARP. In addition to sensitising cells to ionizing radiation and certain chemotherapeutic agents, olaparib and other PARP inhibitors exhibits striking cytotoxicity towards cancer cells deficient in BRCA1, BRCA2, or certain other DNA-repair genes. In my talk, I will explain how we are searching for additional DNA-repair vulnerabilities in cancer cells and how we are defining mechanisms by which cancers can evolve resistance to PARP inhibitors and other molecularly-targeted agents. Finally, I will explain how such knowledge is not only providing us with fundamental insights into DNA-repair mechanisms but is also identifying new opportunities that might be exploited clinically.