Targeting the DNA damage response to enhance radiotherapy in soft tissue sarcomas

Radiotherapy plays an important role in treating non-metastatic soft tissue sarcomas by inducing DNA damage and subsequent cell death. However, all cells possess defence mechanisms to repair DNA damage via DNA damage response (DDR) pathways. Inhibition of these DDR pathways may enhance tumour sensitivity to radiation, potentially improving treatment outcomes. This review assesses the potential of DDR inhibition to enhance radiosensitivity in soft tissue sarcomas, by evaluating both preclinical and clinical studies that combined DDR inhibitors and radiotherapy. Studies were identified by searching literature databases, clinical trial registries and conference abstracts, and focused on the relevance for combining DDR inhibitors and radiotherapy in soft tissue sarcoma treatment. Targeting DDR pathways through key proteins like PARP, ATM and ATR appears to be a promising approach to increase the radiosensitivity of soft tissue sarcomas in preclinical studies with minimal increased toxicity. Although phase I and II clinical trials observed that DDR inhibitors are mostly well tolerated, phase II trials observed limited to no improvement in disease control or overall survival. Moreover, some trials observed increased severe toxicities, especially at higher radiation doses or accelerated schedules. Nevertheless, DDR inhibitors have a great potential to sensitize soft tissue sarcomas to radiotherapy. Unfortunately, the currently developed DDR inhibitors have shown limited effect on overall survival and recurrence rates. Therefore, efforts should be made to either improve their efficacy or to reduce radiation doses through DDR inhibitor-mediated radiosensitization while maintaining efficacy.