Study identifies PARG as a new target to enhance chemotherapy in colorectal cancer

Colorectal cancer is one of the most prevalent tumours and a leading cause of cancer-related mortality. Despite advances achieved in recent years, resistance to available treatments remains one of the main clinical challenges, particularly in advanced stages of the disease.

A study led by researchers from the Resistance, Chemotherapy and Predictive Biomarkers (RCPB) group at the Germans Trias i Pujol Research Institute (IGTP), published in Clinical and Translational Medicine, provides new evidence on how to improve the efficacy of one of the most widely used chemotherapy combinations in clinical practice for the treatment of colorectal cancer: 5-fluorouracil and irinotecan (FUIRI).

The study was carried out within the framework of a project of excellence funded by the Instituto de Salud Carlos III (ISCIII) and managed by the IGTP, with the participation of several collaborating groups. The project was initiated at the IGTP and developed in collaboration with the Josep Carreras Leukaemia Research Institute (IJC), as well as with the group led by Dr Sonia Forcales, who is currently affiliated with the University of Barcelona (UB).

Identifying resistance mechanisms to improve therapeutic response

The FUIRI combination works by inducing DNA damage in tumour cells with the aim of triggering cell death. However, many cancer cells develop internal mechanisms that allow them to repair this damage and survive treatment, thereby limiting its effectiveness.

In this context, the study focused on chromatin regulatory factors, a group of proteins that control the organisation of DNA within the cell and its accessibility. These factors play a key role in the cellular response to genetic damage and can directly influence tumour sensitivity to chemotherapy.

Using a loss-of-function genetic screen, the research team systematically analysed more than 900 genes related to chromatin regulation in colorectal cancer cells. This approach enabled the identification of genes that contribute to resistance to FUIRI treatment.

PARG, a promising new therapeutic target

Among the genes identified, the enzyme PARG (poly-ADP-ribose glycohydrolase), which is involved in DNA damage repair, emerged as a key factor. Experimental results showed that inhibition of PARG, through both genetic and pharmacological strategies, significantly increases the cytotoxic effect of chemotherapy.

Specifically, PARG inhibition enhanced cell death and apoptosis in different colorectal cancer models when combined with 5-fluorouracil and irinotecan, both in cell cultures and in animal models. In addition, analysis of tumour samples from patients revealed that high PARG expression is associated with poorer treatment response, a higher incidence of liver metastases and reduced long-term survival.

Towards new combined therapeutic strategies

Overall, the findings position PARG as a potential new therapeutic target in colorectal cancer and open the door to the development of combined strategies integrating PARG inhibition with standard chemotherapy. This approach could help overcome resistance mechanisms and improve patient responses to existing treatments.

As explained by Eva Martínez-Balibrea, principal investigator of the group at the IGTP and the Institut Català d’Oncologia (ICO), and leader of the study:"This is the first study to demonstrate that combining PARG inhibition with 5-fluorouracil- and irinotecan-based chemotherapy could be an effective strategy in patients with metastatic colorectal cancer. Several PARG inhibitors are currently in phase I and II clinical trials, opening up the possibility that these findings could be translated into clinical practice within a relatively short timeframe."