Mechanisms of radioresistance and strategies for radiosensitization in ovarian clear cell carcinoma

DESCRIPTION Ovarian clear-cell carcinoma (OCCC) is the second most common type of ovarian cancer and is associated with poor survival because of the lack of effective therapeutic options. Our long-term goal is to understand the molecular mechanisms that create therapeutic opportunities in OCCC and to translate such discoveries into meaningful clinical applications. ARID1A, a component of the chromatin remodeling complex SWI/SNF, is mutated in more than 50% of OCCC. With the support of our current R01 project, we have established a successful research program to study the role of the ARID1A-SWI/SNF complex in regulating the DNA damage response (DDR) and DNA repair. In the preliminary studies leading to this renewal application, we discovered a new role for the ARID1A-SWI/SNF complex in transcriptional silencing of heterochromatin repetitive DNA sequences, namely satellite DNA element (satDNA) in response to ionizing radiation (IR)-induced DNA damage. We also showed that aberrant IR-induced satRNA expression activates RNA-sensing innate immune response in ARID1A-deficient cells. These exciting and promising findings have led us to hypothesize that ARID1A deficiency unleashes IR- induced de-repression of heterochromatin repetitive satDNA sequences by impairing DNMT3A-mediated DNA methylation and transcriptional silencing. This consequently activates the dsRNA-sensing RIG-1/MDA5 pathway, and provides the rationale to use ATM inhibitors to enhance the efficacy of radiotherapy and immunotherapy by selectively modulating nucleic acid-mediated innate immune response in ARID1A-deficient tumors. We will employ multidisciplinary approaches, including molecular/biochemistry/cell biology-based mechanistic studies, shRNA/CRISPR-Cas9-based genetic studies, bioinformatic analysis and preclinical animal model-based translational studies, and analysis of OCCC patient samples to test this hypothesis. Together, our proposed project will not only mechanistically advance our fundamental understanding of the underlying biology of how the ARID1A-SWI/SNF chromatin remodeling complex maintains heterochromatin transcriptional silencing to radiation-induced DNA damage, but will also develop new personalized immune- based radiotherapy regimens tailored to the genetic contexts of tumors, such as ARID1A deficiency or more broadly SWI/SNF-mutated cancers.