U of T researchers pinpoint key issue with common chemotherapy drug, identify new potential therapeutic targets for pancreatic cancer

Researchers at the University of Toronto’s Donnelly Centre for Cellular and Biomolecular Research have found two enzymes that work against the chemotherapy drug gemcitabine, preventing it from effectively treating pancreatic cancer.

The enzymes, APOBEC3C and APOBEC3D, increase during gemcitabine treatment and promote resistance to DNA replication stress in pancreatic cancer cells. This counteracts the effects of gemcitabine and, in fact, allows for the growth of cancer cells.

The findings were recently published in the journal Nature Cancer.

“Pancreatic cancer has proven to be very challenging to treat, as it is usually diagnosed at stage 3 or 4,” said Tajinder Ubhi, first author on the study and former PhD student in biochemistry at U of T’s Temerty Faculty of Medicine. “It is the most lethal type of cancer in Canada, with an average survival time of less than two years. While chemotherapy with gemcitabine has increased survival by a few months in clinical trials, options for treatment of pancreatic cancer remain limited.”

Replication stress is the key process by which gemcitabine stops cancer cells from continuing to multiply. It involves the dysregulation of DNA replication, which occurs when cells divide. Replication stress can transform a healthy cell into a cancerous one, but can also be activated within cancer cells to eliminate them.

Gemcitabine has been used for nearly three decades to treat a wide variety of cancers, including pancreatic, breast and bladder cancer. A downside of it targeting dividing cells is that it can produce toxic side effects in tissues that aren’t being targeted for treatment.

Ubhi and other members of Professor Grant Brown’s lab at the Donnelly Centre have been working towards understanding the possible causes of replication stress and its impacts. One way to do this is by studying the stress response mechanisms in cancer cells treated with gemcitabine.

“We conducted a genome-wide CRISPR screen to find genes that could increase the sensitivity of pancreatic cancer cells to gemcitabine,” said Brown, professor of biochemistry at the Donnelly Centre and principal investigator on the study. “We were excited to identify APOBEC3C and APOBEC3D because other enzymes in the APOBEC3 family can cause cancers to eventually become resistant to treatment. We discovered a more direct role for the enzymes, where they actually protect pancreatic cancer cells from gemcitabine therapy.”

Neither enzyme is naturally found at high concentrations within healthy or cancerous cells. The Catch-22 of gemcitabine is that the replication stress it causes in pancreatic cancer cells in turn triggers an increase in both enzymes. The research team found that removing either APOBEC3C or APOBEC3D kills pancreatic cells by stymieing DNA repair and destabilizing the cell genome.

“What is most exciting is that the removal of just APOBEC3C or APOBEC3D is enough to stop the replication of gemcitabine-treated pancreatic cancer cells,” said Ubhi. “This indicates that the enzymes could be effective new targets for treating this form of cancer.”

This research was supported by the Canada Foundation for Innovation, the Canadian Cancer Society, Canadian Friends of the Hebrew University, the Canadian Institutes of Health Research, Cold Spring Harbor Laboratory, the Government of Ontario, the Lustgarten Foundation, the Ministry for Culture and Innovation of Hungary, the National Institutes of Health, the Northwell Health Affiliation, the Ontario Institute for Cancer Research, Pancreatic Cancer Canada, the Princess Margaret Cancer Foundation, the Simons Foundation, the Terry Fox Research Institute and the Thompson Foundation.