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Mystery Behind 5-FU Resistance Solved

According to a recent study, the Bok protein from the BCL-2 protein family was discovered to play a role in resistance to the chemotherapy drug 5-fluorouracil (5-FU).

An antimetabolite, 5-FU is an important drug used for many cancers including colorectal cancer, breast cancer, gastrointestinal cancer, head and neck cancer, neuroendocrine tumors, thymic cancers, cervical cancer, and bladder cancer, among others. 5-Fluorouracil works by incorporating toxic substances into cancerous cells, disrupting their ability to divide, which ultimately leads to their death. Acquired 5-FU resistance occurs in up to 50% of colorectal cancer patients, making this issue a major concern.

In this study, published in Proceedings of the National Academy of Sciences of the United States of America, the researchers tested rectal and peritoneal cancer tissue samples taken from cancer patients undergoing surgery, including those who had resistance to 5-FU. One of the study authors, Hamsa Puthalakath, PhD, Associate Professor of Biochemistry at La Trobe University, explained how Bok is involved in 5-FU resistance: "…Bok binds with an enzyme called UMPS, enhancing cells' ability to proliferate. Without BOK, cells struggle to synthesize DNA, and they can't proliferate. The same enzyme is also responsible for converting 5-FU into its toxic form in cancer. Therefore, to avoid 5-FU's toxicity, cancer cells turn off Bok."

Then, cancer cells become dormant, surviving the toxicity of 5-FU, and mutate to become resistant to 5-FU.

This research reveals that Bok is a biomarker for predicting 5-FU response. A potential lab test can be developed to test for this protein. In addition, further research is underway to discover how to make 5-FU effective in cases where resistance builds to the drug.

"In understanding the science behind chemotherapy resistance, we think that we have found cancer's 'Achilles heel' and this has significant implications for future drug development," Dr. Puthalakath commented.

For More Information

Srivastava R, Cao Z, Nedeva C, et al (2019). BCL-2 family protein BOK is a positive regulator of uridine metabolism in mammals. Proc Natl Acad Sci U S A. [Epub ahead of print] DOI:10.1073/pnas.1904523116

Image Courtesy of Fight Colorectal Cancer (blog)

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