DTX2: A New Weapon Against the Resistance to Radiotherapy and PARP inhibitors

The Université de Sherbrooke Cancer Research Institute (IRCUS) has the pleasure to announce that Billel Djerir has been awarded the IRCUS Award for Best 2024 Cancer Article. In his article, the findings highlight the role of DTX2, a ligase E3 protein from the Deltex family as a new regulator for the repair of DNA double-strand breaks. Moreover, DTX2 could help cancer cells resist to X-rays irradiation, the type of radiation used in radiotherapy, and to olaparib, a PARP enzyme inhibitor that completely transformed the treatment of cancers linked to BRCA gene mutations.

This award recognizes the scientific quality and the impact of the article published in the scientific Journal of Biological Chemistry, by Billel Djerir as first author, a PhD student who recently graduated at IRCUS in the Department of Biology of the Sciences.

First step: Developing the technology

An innovative strategy had to be designed to characterize a new and unexpected player: the DTX2 protein, a ligase E3 protein from the Deltex family. The high-precision approach combines confocal microscopy and laser micro-irradiation to observe the response to DNA damage in real time. This method enables generating preferentially double-strand breaks (DSBs) in the DNA of living cells; these breaks result in a visible line across their nuclei, and it is possible to observe in real time the proteins that are specifically recruited there.

The expertise that we have developed in the laboratory resulted in the creation of several collaborations with researchers in other universities, who have an interest in studying the response to DNA damages in cancer.

Billel Djerir

DTX2 depends on PARP enzymes to repair DNA

The rapid relegalization of the DTX2 protein to DSB sites was found to be dependent of poly-ADP -ribosylation (PARylation), a signal produced by PARP enzymes. These findings were obtained with the use—among others—of olaparib, a PARP enzyme inhibitor.

Lack of DTX2 decreases the efficiency of DSB repairs by homologous recombination

It was shown that DTX2 was necessary to ensure an efficient repair of DSBs using the homologous recombination (HR) pathway. Without DTX2, key proteins regulating this pathway—including BRCA1—are less efficiently assembled at the sites of ionizing radiation-induced (X-rays induced) DNA damage. Without DTX2, the DSB repairs through the HR pathway become defective.

Absence of DTX2 increases the sensitivity to X-rays and olaparib

When cancer cells do not have DTX2, they become significantly more sensitive to the irradiation by X-rays. Therefore, DTX2 would be a potential and promising target to offset the resistance to radiotherapy or would be used perhaps as a biomarker to predict the resistance.

Since its approval in the United States in 2014, olaparib has revolutionized the treatment of ovarian, breast and prostate cancers with the BRCA mutation (BRCA1 or BRCA2) found in only 5–15% of cases, resulting in a defective HR repair. Numerous PARP inhibitors are currently in development.

The removal of DTX2 make the cancer cells significantly more sensitive to olaparib in the absence of a BRCA mutation; this could represent a new treatment option for 85–95% of ovarian, breast and prostatic cancers. DTX2 could potentially help re-sensitize the BRCA-mutated cancers that became resistant to olaparib, a particularly common phenomenon observed in advanced ovarian cancers.

The IRCUS Award for best 2024 cancer article is a prestigious reward that not only showcases a remarkable scientific finding, but also highlights years of efforts, rigour and passion. For Billel Djerir, it is the outcome of doctoral studies driven by tireless curiosity, and a deep desire to advance basic research on cancer resulting in concrete breakthroughs filled with hope.

An Impactful new student generation

The executive of IRCUS and the Comité d’animation scientifique et sociale de l’IRCUS (CASSI - scientific and social animation committee of IRCUS), in charge of organizing the contest, want to acknowledge on the excellency of its new student generation by revealing which papers were ranked second and third.

2^nd position: Maude Hamilton | PhD student in the laboratory of Véronique Giroux, Professor and Researcher at IRCUS at the Faculty of Medicine and Health Sciences. The article published in 2024 in the journal Biology Open shows that the overexpression of the ASCL2 transcription factor in mouse esophageal organoids reduces the ability of normal cells to multiply. Moreover, this overexpression would render these cells more resistant to radiotherapy and to cisplatin-, fluorouracil-, and camptothecin-based chemotherapy. These results could open a path to new therapeutic strategies for the esophageal cancer.

3^rd position: Wiam El Kheir | PhD student; she recently graduated under the co-direction of Nathalie Faucheux, Professor and Researcher at IRCUS at the Faculty of Engineering, and Benoît Paquette, Professor and Researcher at IRCUS at the Faculty of Medicine and Health Sciences. The article published in the journal PLoS One in 2024 describes the 3D-dynamic modelling of a glioblastoma, integrating the gradients of chemokines and conditions simulating the movement of the interstitial fluid.

This in vitro model reproduces a more realistic tumour microenvironment for the study of glioblastoma cell migration. The aim is to design an effective gel that could imprison the cancer cells and kill them when they cannot be surgically removed.

IRCUS is proud to train an audacious scientific generation that can combine creativity and scientific rigour to develop innovative solutions matching the complex challenges of cancer.