Abstract LB-217: A gene signature that predicts deficiency of homologous recombination DNA repair

DNA repair pathways play a fundamental role to maintain genomic stability. Defects in specific DNA repair pathways predispose to cancer development, but also provide therapeutic opportunities: for example, poly-ADP ribose polymerase (PARP) inhibitors are synthetically lethal with cancer cells, which are defective in homologous recombination (HR)-mediated DNA repair, such as BRCA1/BRCA2-deficient tumors. However, recent clinical trials of PARP inhibitors have shown rather disappointing results, particularly in the treatment of triple-negative breast cancer (TNBC), which has a molecular phenotype similar to that of BRCA-deficient breast cancer. As a targeted therapy, the clinical success of PARP inhibitors is dependent on identifying cancer cells with HR repair deficiency. Thus the observations of PARP inhibitors from clinical trials raise a key question: Can we identify a molecular signature of HR repair deficiency in cancer cells? To answer this question, we utilized the gene expression profiling approach to measure the cellular transcriptional reprograming in HR-deficient cell lines. By analyzing the molecular changes of transcriptional landscape, we identified an HR-defect gene signature that predicted HR repair deficiency in cells, predicted clinical outcomes of multiple human cancers, and predicted sensitivity of human cancer cells to PARP inhibitors. HR repair deficiency leads to genomic instability and often promotes accumulation of additional mutations. Our gene signature analysis further revealed that combinatorial effects of co-existing genetic changes such as loss of both BRCA1 and PTEN may extensively rewire the HR repair network and confer resistance to PARP inhibitor treatment. Moreover, to combat PARP inhibitor resistance, we successfully used our HR-defect gene signature as a drug discovery tool and found that TTK, mTOR and PI3K inhibitors could induce HR repair deficiency and sensitize cancer cells to PARP inhibitor treatment. Collectively, our findings demonstrate that transcriptional signature can be used to define the functional status of the HR repair network in cells. In summary, our study identifies a gene signature of HR repair deficiency, which provides a novel network view of the DNA repair process. In addition to using our gene signature as a prognostic marker for multiple cancers including breast, ovarian and lung cancer, our findings potentially have a significant impact on predicting responsiveness and overcoming resistance to targeted therapeutic regimens with DNA repair inhibitors such as PARP inhibitors. Citation Format: Guang Peng, Gordon Mills, Shiaw-Yih Lin. A gene signature that predicts deficiency of homologous recombination DNA repair. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-217. doi:10.1158/1538-7445.AM2013-LB-217