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Abstract 3497: SAMHD1 is a Novel Biomarker and Therapeutic Target for Radiation Therapy and PARP Inhibition in Breast Cancer

SAMHD1 is a Novel Biomarker and Therapeutic Target for Radiation Therapy and PARP Inhibition in Breast Cancer Ashley Schlafstein, Waaqo Daddacha, David S. Yu Background/Introduction: Patients with breast cancer are often treated by ionizing radiation (IR) and PARP inhibitors; however, the effectiveness of these treatments is often limited by lack of response and/or resistance. Sterile alpha motif and HD domain-containing protein 1 (SAMHD1) is a deoxyribonucleotide triphosphate (dNTP) triphosphohydrolase with a well-established role in HIV-1 restriction by depleting dNTPs required for reverse transcription and replication. SAMHD1 is also dysregulated in breast and other cancers and in autoimmune disease. In addition to its well-established dNTPase activity, our lab has defined a novel role for SAMHD1 in DNA end resection to facilitate DNA double strand break (DSB) repair by homologous recombination (HR). Because of its role in DNA DSB repair and its link to breast cancer, we hypothesized that SAMHD1 could be used as a novel biomarker and target for breast cancer therapy. Methods: We queried the TCGA database for patients with breast cancer who were treated with or without IR to determine if there was an association of SAMHD1 expression level with clinical outcome. We also determined if targeting SAMHD1 for proteasomal degradation with novel virus like particles (VLPs) containing Vpx, a viral accessory protein, can sensitize breast cancer cells and tumors to DNA damaging agents. Results: In patients with breast cancer treated with IR, low SAMHD1 expression was associated with a statistically significant improvement in overall survival, while for those not treated with IR, no significant difference in association of SAMHD1 expression with outcome was observed. Breast cancer cells and tumors treated with VLPs containing Vpx were hypersensitive to IR and PARP inhibitor. Conclusion: Our results identify SAMHD1 as a novel biomarker for stratifying breast cancer patients for treatment with IR. In addition, targeting SAMHD1 with VLPs containing Vpx may be a novel therapeutic strategy for sensitizing breast cancer to IR, PARP inhibitors, and other agents that induce DNA DSBs. Citation Format: Elizabeth Thompson. SAMHD1 is a Novel Biomarker and Therapeutic Target for Radiation Therapy and PARP Inhibition in Breast Cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3497.