Radiation Biology

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SU_36_2364 - Preclinical Models of DNA Repair Deficiency in Prostate Cancer

Sunday, October 21
1:15 PM - 2:45 PM
Location: Innovation Hub, Exhibit Hall 3

Preclinical Models of DNA Repair Deficiency in Prostate Cancer
K. Fitzpatrick1, J. Hwang2, M. Y. Cai1, D. Liu1, B. Kochupurakkal1, E. Van Allen1, A. D. DAndrea3, and K. Mouw4; 1Dana Farber Cancer Institute, Boston, MA, 2Broad Institute of MIT and Harvard, Cambridge, MA, 3Dana Farber Cancer Insitute, Boston, MA, 4Dana-Farber Cancer Institute, Brigham and Women's Hospital, Boston, MA

Purpose/Objective(s): DNA repair pathways alterations are common in prostate tumors and have important implications for prognosis and therapy selection. However, the clinical impact of specific DNA repair mutant alleles are often uncertain, and the mechanisms by which DNA repair deficiency drives prostate cancer tumorigenesis and therapy response are poorly understood. We hypothesize that studying the impact of DNA repair pathway deficiency in prostate preclinical models may uncover relevant biology and identify unique therapeutic opportunities.

Materials/Methods: We have assembled a large panel of immortalized DNA repair deficient cell lines, representing multiple DNA repair genes and pathways. These cell lines provide a tractable system to test the functional impact of mutations in a wide variety of DNA repair genes. By expressing WT or mutant versions of the DNA repair gene of interest in the corresponding repair-deficient parental cell line, we are able to quantify the ability of individual DNA repair alleles to support cellular DNA repair. In addition, we are using CRISPR/Cas9 technology to delete DNA repair genes in a variety of prostate epithelial and tumor cell lines.

Results: Using isogenic DNA repair proficient/deficient cell pairs, we find that many clinically observed missense mutations in DNA repair genes such as ATM and FANCD2 confer functional DNA repair deficiency. To further study the role of ATM loss in prostate cancer, we have created ATM knockout clones in multiple prostate-derived cell lines, and we find that the ATM-deficient lines exhibit features consistent with loss of DNA double-strand break checkpoint signaling, including sensitivity to ionizing radiation. However, unlike cell lines with loss of upstream homologous recombination genes such as BRCA1/2, ATM-deficient cells do not exhibit increased sensitivity to PARP inhibitors, but do have increased sensitivity to ATR inhibitors. On-going efforts are aimed at further characterizing the sensitivity profiles of DNA repair deficient lines and investigating the interplay of DNA repair loss and hormone signaling.

Conclusion: Loss of DNA repair pathway function has important implications for prostate cancer prognosis and treatment. However, the functional landscape of DNA repair alterations across prostate cancer is poorly defined and the role of DNA repair mutations in driving prostate cancer biology and therapy response is incompletely understood. Our data suggest that many commonly observed DNA repair mutations identified in prostate tumors are functionally deleterious and are sufficient to drive changes in the prostate tumor phenotype, which may have important implications for therapy selection in this subset of prostate cancer patients.

Author Disclosure: K. Fitzpatrick: None. J. Hwang: None. M. Cai: None. B. Kochupurakkal: None. E. Van Allen: None. K. Mouw: Advisory Board; Pfizer, EMD Serono.

Kenyon Fitzpatrick, BS

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