Targeting the DNA Damage Response and DNA Repair Pathways to Enhance Radiosensitivity in Colorectal Cancer

by Selleckchem | Oct 17 2023

Radiotherapy is an important component of current treatment options for colorectal cancer (CRC). It is either applied as neoadjuvant radiotherapy to improve local disease control in rectal cancers or for the treatment of localized metastatic lesions of CRC. DNA double-strand breaks (DSBs) are the major critical lesions contributing to ionizing radiation (IR)-induced cell death. However, CRC stem cells promote radioresistance and tumor cell survival through activating cell-cycle checkpoints to trigger the DNA damage response (DDR) and DNA repair after exposure to IR. A promising strategy to overcome radioresistance is to target the DDR and DNA repair pathways with drugs that inhibit activated cell-cycle checkpoint proteins, thereby improving the sensitivity of CRC cells to radiotherapy. In this review, we focus on the preclinical studies and advances in clinical trials of DNA-dependent protein kinase catalytic subunit (DNA-PKcs), ataxia telangiectasia mutated (ATM), ataxia telangiectasia and Rad3-related kinase (ATR), checkpoint kinase 1 (CHK1), checkpoint kinase 2 (CHK2), WEE1 and poly (ADP-ribose) polymerase 1 (PARP1) kinase inhibitors in CRC. Importantly, we also discuss the selective radiosensitization of CRC cells provided by synthetic lethality of these inhibitors and the potential for widening the therapeutic window by targeting the DDR and DNA repair pathways in combination with radiotherapy and immunotherapy.

Comments:

Radiotherapy plays a crucial role in the treatment of colorectal cancer (CRC), particularly in rectal cancers and localized metastatic lesions. It works by inducing DNA double-strand breaks (DSBs), which are critical lesions that contribute to the death of cancer cells upon exposure to ionizing radiation (IR). However, CRC stem cells have been found to promote radioresistance and cell survival by activating cell-cycle checkpoints that trigger the DNA damage response (DDR) and DNA repair mechanisms following radiation exposure.

To overcome radioresistance and improve the effectiveness of radiotherapy, researchers have explored targeting the DDR and DNA repair pathways using specific drugs that inhibit activated cell-cycle checkpoint proteins. Several proteins have been identified as potential targets, including DNA-dependent protein kinase catalytic subunit (DNA-PKcs), ataxia telangiectasia mutated (ATM), ataxia telangiectasia and Rad3-related kinase (ATR), checkpoint kinase 1 (CHK1), checkpoint kinase 2 (CHK2), WEE1, and poly (ADP-ribose) polymerase 1 (PARP1).

Numerous preclinical studies have investigated the efficacy of inhibitors targeting these proteins in CRC. Additionally, clinical trials have been conducted to assess their potential in combination with radiotherapy. The goal is to enhance the sensitivity of CRC cells to radiotherapy by inhibiting the DDR and DNA repair pathways. By blocking these pathways, it becomes possible to prevent the repair of DNA damage induced by radiotherapy, leading to increased cancer cell death.

Furthermore, researchers have explored the concept of synthetic lethality, where the combination of two or more inhibitors targeting different components of the DDR and DNA repair pathways can selectively sensitize CRC cells to radiation. This approach exploits the dependency of cancer cells on specific pathways for survival and utilizes the inhibition of multiple targets to induce synthetic lethality, making cancer cells highly susceptible to radiotherapy.

In addition to radiotherapy, there is growing interest in combining DDR and DNA repair pathway inhibitors with immunotherapy, aiming to widen the therapeutic window and improve treatment outcomes. The rationale is that by impairing the DDR and DNA repair pathways, tumor cells become more immunogenic, making them vulnerable to the immune system's attack. Combining these approaches holds promise for enhancing the effectiveness of both radiotherapy and immunotherapy in the treatment of CRC.

Overall, the targeted inhibition of DDR and DNA repair pathways in combination with radiotherapy represents an exciting area of research in CRC treatment. Preclinical studies and ongoing clinical trials are providing valuable insights into the efficacy and potential of these inhibitors, both as standalone therapies and in combination with other treatment modalities like immunotherapy.