Dissecting the Role of ATRX in Soft Tissue Sarcoma Development and Therapeutic Response

Abstract

ATRX is one of the most frequently altered genes in soft tissue sarcoma, with alterations occurring in 29% of these tumors. However, the role of ATRX in the development and response to cancer therapies in soft tissue sarcoma remains poorly understood. Here, we developed a primary mouse model of soft tissue sarcoma and studied the effect of Atrx deletion on tumor development and therapeutic response. Our findings demonstrate that Atrx deletion regulates tumor development and increases sarcoma sensitivity to radiation therapy. In the absence of Atrx, irradiated sarcomas have increased persistent DNA damage, telomere dysfunction, and mitotic catastrophe. We find that Atrx deleted tumors have impaired cGAS-STING signaling, with accompanying sensitivity to the novel clinical therapy oncolytic herpesvirus. Translation of these results to patients with ATRX mutant cancers could enable genomically-guided cancer therapeutic approaches that improve patient outcomes.