LAUSR

Nearly every cancer patient, especially those with highly lethal and aggressive tumor types, is treated with cytotoxic chemotherapy. Currently, the selection of chemotherapy is based on average responses over a large number of patients. This belies our understanding of DNA repair that has demonstrated that the inability of a tumor cell to properly repair particular types of DNA damage has a dramatic influence on cell survival. Here, we report the generation of a quantitative chemical-genetic interaction map to chart the influence of knockdown of 625 genes on sensitivity to 30 FDA approved chemotherapeutic agents in breast epithelial cells. The resulting map highlights key genes which, when mutated or deleted in tumor cells, can dramatically induce sensitivity or resistance to particular DNA damaging agents. Interrogation of this map reveals new DNA repair factors that are recurrently deleted in breast and ovarian cancers, provides a platform for prediction of cancer cell line responses from genomic data and provides the basis for the prioritization of new drug combinations. Our data reveal that the loss of ARID1A, a key component of the SWI/SNF chromatin remodeling complex, drives resistance to cisplatin as well as PARP inhibition. Mechanistically, we uncover that ARID1A functions as a suppressor of DNA repair by homologous recombination (HR) and that its loss via mutation or deletion rescues HR in a BRCA1 independent fashion. Together, our data indicates a plethora of potential biomarkers for chemotherapy response and provides an opportunity for computational integration of chemical-genetic networks with patient genomic data to predict optimal chemotherapeutic regimes. This abstract is also being presented as Poster A14. Citation Format: Hsien-Ming Hu, Sourav Bandyopadhyay. Identifying factors mediating response and resistance to chemotherapy through a chemical-genetic interaction map [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr PR07.