Researchers at the University of Toronto’s Donnelly Centre for Cellular and Biomolecular Research have made a significant discovery that could impact the effectiveness of a common chemotherapy drug, gemcitabine, in treating pancreatic cancer.

The study, led by first author Tajinder Ubhi, identified two enzymes, APOBEC3C and APOBEC3D, that hinder the ability of gemcitabine to effectively combat pancreatic cancer cells. These enzymes increase during gemcitabine treatment, promoting resistance to DNA replication stress and ultimately allowing the cancer cells to continue growing.

Pancreatic cancer is known for its difficulty to treat, often being diagnosed at advanced stages with limited treatment options. Despite gemcitabine showing some increase in survival rates in clinical trials, the overall outlook for pancreatic cancer patients remains grim, with an average survival time of less than two years in Canada.

The findings of the study were published in the journal Nature Cancer, shedding light on the underlying mechanisms that compromise the efficacy of gemcitabine in combating pancreatic cancer.

Gemcitabine, a chemotherapy drug used for nearly three decades to treat various cancers, works by inducing replication stress in cancer cells, thereby halting their proliferation. However, the study revealed that the increased levels of APOBEC3C and APOBEC3D counteract the effects of gemcitabine, undermining its ability to impede the growth of pancreatic cancer cells.

Professor Grant Brown, leading the research at the Donnelly Centre, emphasized the significance of the discovery, highlighting the potential impact of the identified enzymes on the resistance of cancers to treatment. The research team utilized a genome-wide CRISPR screen to pinpoint genes that could enhance the sensitivity of pancreatic cancer cells to gemcitabine, ultimately identifying the crucial role played by APOBEC3C and APOBEC3D.

This breakthrough in understanding the resistance mechanisms of pancreatic cancer cells to gemcitabine could pave the way for the development of targeted therapies to overcome the limitations posed by these enzymes, potentially improving the treatment outcomes for pancreatic cancer patients.