LAUSR

Precision therapeutics can be defined as the ability to prescribe effective (curative) therapies only to those patients who will respond, while limiting toxicity to normal tissues and minimizing side effects. The paradigm for precision therapeutics is the BCR-ABL inhibitor imatinib (Gleevec) approved in 2001 for the treatment of Philadelphia chromosome-positive chronic myelogenous leukemia (CML). As DNA-damaging agents have been approved before the era of precision medicine, their use remains empirical. Some patients respond remarkably well while others only suffer from the drug side effects. The possibility of using DNA-damaging agents in the context of precision medicine changed with the approval of the poly(ADPribose) polymerase (PARP) inhibitors, which have been approved for patients with BRCA deficiencies and prior response to platinum drugs, and act as DNA-damaging agents by trapping PARP1 and PARP2 on DNA lesions. We will review the use of cancer cell line genomics to discover novel determinants of response to DNA-targeted agents, and to elaborate molecular signatures of response. We will also discuss the broad implications of the discovery of Schlafen 11 (SLFN11) as a novel determinant of response to PARP inhibitors, platinum derivatives, topoisomerase inhibitors, gemcitabine, hydroxyurea, and cytosine arabinoside. We will demonstrate the use of our novel crossdatabase (cdb) web-based tools to mine genomics and pharmacologic determinants of response and genomic signatures for anticancer drugs (https://discover.nci.nih.gov/cellminercdb). Citation Format: Yves G. Pommier, William C. Reinhold, Junko Murai, Anish Thomas. Precision therapeutics with DNA-damaging agents [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr CN05-03.