Fundamental research with major clinical potential
Important research from the laboratory of Dr. Javier Di Noia, Director of the Molecular Biology of B Cells Research Unit at the Montreal Clinical Research Institute (IRCM), published in the prestigious scientific journal PNAS, opens the door to a better understanding of how cells manage DNA building blocks and the role of a novel enzymatic reaction in anti-cancer therapies. This work is yet another demonstration of the importance of basic research in the development of life-saving therapies.
The research team has identified a previously unknown metabolic reaction in human cells. This discovery not only alters our understanding of the mechanisms underlying the metabolism of DNA building blocks (also known as nucleotides), but also plays an important role in mitigating the toxicity of certain anti-cancer drugs.
In depth
The group showed that the enzyme CDADC1, found only in vertebrates, converts dCTP, a DNA precursor, into dUTP, a base rarely found in DNA. Although CDADC1 is not required for normal cell growth or survival in mice, its activity reveals a hidden layer of DNA metabolism that holds significant implications for cancer therapy.
The team discovered that CDADC1 also acts on gemcitabine and decitabine, two common chemotherapy drugs that closely resemble dCTP.
A direct link to cancer therapies
Gemcitabine is used to treat pancreatic, lung, breast and other cancers, while decitabine is used to treat leukemia. CDADC1 modifies the active form of these drugs, making them more easily deactivated and thus less effective against cancer cells. Eliminating CDADC1 in tumors significantly enhances drug efficacy in mouse models of pancreatic cancer, providing a potential strategy for overcoming resistance to treatment. However, this approach carries a major risk: CDADC1-deficient mice, generated by the laboratory exhibited severe, even fatal, toxicity following gemcitabine administration.
These findings suggest that patients lacking CDADC1 expression or activity, an expected occurrence, given human genetic heterogeneity, may be at high risk of severe toxic effects when treated with these drugs. This could explain a subset of currently unexplained hypersensitivity to gemcitabine or decitabine.
This discovery makes CDADC1 an important new determinant of chemotherapy response and safety, highlighting the need to assess CDADC1 status in patients before initiating treatment with gemcitabine or decitabine.
The importance of this discovery lies in the uncovering a determinant of chemotherapy toxicity currently not known in the clinic and its consequences on treatment.
In short, why is this work important?
- The Di Noia laboratory has discovered that CDADC1 may play a crucial role in the efficacy and safety of certain anti-cancer treatments.
- This could enable treatments to be better tailored to individual patients:
- Targeted blockade of CDADC1 in tumors could boost the effect of drugs in resistant patients.
- On the other hand, the discovery implies the need to assess CDADC1 status in patients before treatment with gemcitabine or decitabine to prevent systemic toxicities.
- This is potentially a major advance in personalized medicine, which could make certain chemotherapies more effective and safer.
Note that subsequent work will be needed to refine this understanding.
Article:
PNAS article #2024-24409R (CDADC1 is a vertebrate-specific dCTP deaminase that metabolizes gemcitabine and decitabine to prevent cellular toxicity)
