PARG inhibition slows HCC progression, boosts efficacy of immune checkpoint therapy

In hepatocellular carcinoma (HCC), poly(ADP-ribose) glycohydrolase (PARG) may serve as an oncogene by modulating PARG/DDB1/c-Myc signaling and be used as a biomarker to identify HCC patients who may derive benefit from anti-PD-1 treatment, suggests a study.

The researchers analysed the pathophysiological role of PARG and assessed the utility of targeting dePARylation for HCC therapy. Two orthotopic xenograft models and a Parg^flox/flox mice model were used to evaluate the oncogenic function of PARG, while the therapeutic efficacy of PARG inhibitors combined with an anti-PD-1 antibody was assessed in murine orthotopic models.

Finally, the researchers examined the pathological relevance of the PARG/DDB1/c-Myc/MMR axis using microarray analysis.

A strong association was seen between high PARG expression and poor HCC prognosis. Deletion of the hepatocyte-specific PARG led to significantly impaired liver tumorigenesis.

PARG also induced HCC growth and metastasis via DDB1-dependent modulation of c-Myc. To be precise, PARG dePARylated DDB1 and then promoted DDB1 autoubiquitination, which led to the stabilization of the c-Myc protein in HCC cells.

Of note, PARG downregulation lessened c-Myc-induced MMR expression, while PARG deficiency was predictive of a favourable prognosis in HCC patients treated with anti-PD-1-based immunotherapy. PARG inhibitors could also act in synergy with anti-PD-1 antibodies in orthotopic mouse models.

“Our findings suggest that co-inhibition of PARG and PD-1 is an effective novel combination strategy for patients with HCC,” the researchers said.