Abstract MS2-2: MS2-2 The latest breakthroughs on the translational aspects of DNA repair pathways

Abstract

Abstract Genomic instability exists in the majority of human cancer, and there is an underlying DNA repair defect driving the instability in most cases. There are seven defined DNA repair pathways that, when inactive, can produce genome wide patterns of mutations. Current cancer genomics can provide a significant insight into the underlying DNA repair defect. This information can be used to select targeted therapies or suggest a more likely response to immune checkpoint blockade. To use acquired homologous recombination (HR) deficiency as an example of this paradigm, we have found that large scale genomic rearrangements and segmental copy number changes are found in breast cancers without a known germline mutation and see a strong link to biallelic alterations in homologous recombination genes. We detected a genetic etiology of HR deficiency in 90% of studied HR-deficient cases, whereas HR-proficient tumors only showed biallelic HR gene mutations in <7% of cases tested. The goal now is to develop genomic biomarkers that could be used to identify cancer patients who would benefit from therapy with PARP inhibitors and other novel agents, such as those identified by studies of synthetic lethality. Synthetic lethality in human cancer is a developing area of new therapeutic discovery. HR deficiency is thought to be rescued by at least 3 different DNA repair pathways: base-excision repair, translesion synthesis and alternative end joining – all of which are active in proliferating cancer cells. In addition, even the canonical end-joining mechanism of Ku heterodimer binding to any double-stranded end is another component of handling DNA lesion intermediates. The reason for this variety of synthetic lethality has to be different critical DNA lesion intermediates. Knowledge of the DNA damage processing and the proteins involved in the rescue of lesions that would be repaired by HR can provide the basis for the identification of novel targets. I will review our progress in making RAD52 a potential target along with other initiatives for new drug discovery. Citation Format: Powell SN. MS2-2 The latest breakthroughs on the translational aspects of DNA repair pathways [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr MS2-2.