Impact of DNA damage response defects in cancer cells on response to immunotherapy and radiotherapy

Abstract

The DNA damage response (DDR) is a complex set of downstream pathways triggered in response to DNA damage to maintain genomic stability. Many tumours exhibit mutations which inactivate components of the DDR, making them prone to the accumulation of DNA defects. These can both facilitate the development of tumours and provide potential targets for novel therapeutic interventions. The inhibition of the DDR has been shown to induce radiosensitivity in certain cancers, rendering them susceptible to treatment with radiotherapy and improving the therapeutic window. Moreover, DDR defects are a strong predictor of patient response to immune checkpoint inhibition (ICI). The ability to target the DDR selectively has the potential to expand the tumour neoantigen repertoire, thus increasing tumour immunogenicity and facilitating a CD8+ T and NK cell response against cancer cells. Combinatorial approaches, which seek to integrate DDR inhibition with radiotherapy and immunotherapy, have shown promise in early trials. Further studies are necessary to understand these synergies and establish reliable biomarkers.

Analysis of Tumor Mutational Burden, Progression-Free Survival, and Local-Regional Control in Patients with Locally Advanced Non–Small Cell Lung Cancer Treated With Chemoradiation and Durvalumab

“…This suggests that the local-regional control benefit imparted by consolidative ICI treatment could minimize the difference in outcomes between patients with and without alterations in DDR genes. Additionally, we assessed a large panel DDR genes that would be anticipated to have variable effects on radiation response . Although we found alterations in ATM to be most common, and multiple lines of evidence have found ATM alterations to impart radiation sensitivity, our analysis may have been underpowered to detect a clinically meaningful difference.…”

Homologous recombination promotes mitotic death to suppress the innate immune response

“…Mutations in HR pathways drive the etiology of diverse cancer types and are frequent in many tumors 63, 64 . Our data suggest tumors harboring such mutations are potentially resistant to immediate mitotic death during mitotic catastrophe.…”

Metal nanoparticles for cancer therapy: Precision targeting of DNA damage

“…Cancer cells typically have relaxed DNA damage sensing/repair capabilities, and importantly, they can bypass cell cycle checkpoints, allowing them to achieve high proliferation rates, which makes them more susceptible to DNA damage, as replication of damaged DNA increases the likelihood of cell death 20 , 21 , 22 . The concept of using DNA as a target has spurred the development of numerous cancer therapies based on DNA damage strategies, such as platinum-based chemotherapy, radiotherapy, and photothermal therapy 23 , 24 , 25 .…”