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For the past ten years or so, APOBEC3 cytidine deaminases (APOBEC) enzymes have emerged as important cancer targets in a number of solid tumor types. Their mutational rate is higher in cancer cells than in normal cells and when they are expressed in cancers, those cancers have a worse prognosis.

“There are probably over 1,000 papers asserting that APOBEC enzymes are pro-tumor, that they are mutational drivers of cancer since they directly mutate the DNA of the cancer cells,” says Mani Larijani, of the department of molecular biology and biochemistry at Simon Fraser University in Canada. Together with Aaron Hata, of Massachusetts General Hospital, the pair published a commentary in Cancer Cell describing the theoretical best time to initiate targeted therapy with APOBEC inhibitors.

In 2023, Hata published a paper in Nature showing in a mouse model of lung cancer that APOBEC enzymes also drive drug resistance. “He showed that the drug itself can induce the expression of resistance,” Larijani explains. A patient takes a chemotherapy drug, which upregulates APOBECs because they are activated by stress and inflammation, and the APOBECs cause new mutations that drive resistance to the treatment. “So not only do APOBECs cause cancers, but this new research also shows that treatment against them can induce even more mutations leading to drug resistance.”

These findings mean that although APOBEC inhibitors remain in development—with none available as a current therapy—understanding the timing and consequences of APOBEC-driven treatment will be critical for guiding the development of anti-cancer therapeutic strategies.

As a biochemist studying the structural function of enzymes, Larijani has long been studying a similar enzyme known as activation-induced cytidine deaminase (AID), an ancestral member of the APOBEC family, for 20 years. His research shows that AID also causes these genome-wide mutations that cause cancer of the immune cells, leading to leukemias and lymphomas.

In his quest to find AID inhibitors for leukemia and lymphomas, Larijani used evolutionary biochemical computation to look at AID structures across a wide range of species. He discovered that the catalytic part of the AID enzyme that causes the mutations is not typical of most enzymes. “Turns out all of these APOBEC enzymes have similar catalytic markers,” he explains. When his team discovered new AID inhibitors, they fortuitously observed they also inhibit APOBEC enzymes.

While many groups and companies have been trying to make APOBEC inhibitors, their structures make them difficult to target. Today’s first-generation inhibitors require significant development to become drugs.  “Yet, we know that these enzymes are good drug targets because they are causing both cancer and drug resistance,” Marijani adds. So thinking ahead, the team cautions users to anticipate and understand the best use case for APOBEC inhibitors.

It’s all about timing, they say, and APOBEC inhibitors should only be given in conjunction with other drugs to thwart drug resistance. One would deliver a therapy to target a pathway in a given cancer. At the same time, an APOBEC inhibitor would be administered to prevent the development of new mutations.

“We caution that the timing is important,” Larijani says, “because you have to add the APOBEC inhibitor right before you give the main drug or just at the same time, so that you do not give that time for those drugs to enhance APOBEC expression and for the APOBECs to drive mutation.”  While the APOBEC inhibitor would not target the initial mutation of a cancer, it would hopefully prevent mutations a cancer accumulates during its evolution.

Adds Larijani, “From when you start giving drugs against a cancer, that cancer has a huge window to develop new mutations that are going to give it more aggressiveness, drug resistance, and that is where we see the best timing for APOBEC inhibition.”

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