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Unlocking Cancer’s Chemo-Resistance

Presence of BOK Protein Key for Positive Treatment Response

A La Trobe University researcher is the first scientist to have unlocked the mystery surrounding why some cancers do not respond to treatment with one of the most effective chemotherapy drugs––5-fluorouracil (5-FU).

According to Associate Professor Hamsa Puthalakath, work is now proceeding toward developing a drug that will make 5-FU effective in cancers that have previously been resistant to treatment. The research could lead to a lab test to check for 5-FU resistance, which would reduce unnecessary chemotherapy treatments.

5-FU, which is included on the World Health Organization’s Model List of Essential Medicines, is used to fight colorectal, breast, head, neck, and aero-digestive cancers. However, acquired resistance in response to treatment is a major problem, and as many as half of colorectal cancer patients become resistant to the drug.

A paper just published in the Proceedings of the National Academy of Sciences (PNAS) describes the precise mechanism by which cancer develops resistance to 5-FU.

Puthalakath links 5-FU resistance to a little-understood protein called “BOK,” whose function has puzzled scientists for decades; many believe its function is redundant.

However, the team’s latest research shows that BOK binds with an enzyme called UMPS, which enhances cells’ ability to proliferate. Without BOK, cells struggle to synthesize DNA, and can’t proliferate. This same enzyme also converts 5-FU into its toxic form in cancer, and to avoid 5-FU’s toxicity, the cancer cells turn off BOK.

The cells then become dormant and take up less toxic 5-FU, and this enables them to survive chemotherapy before they mutate to become even more aggressive.

The researchers tested samples from cancer patients. Patients who had responded to 5-FU treatment were found to have BOK, whereas those who had not responded had no BOK.

The finding illustrates that without the presence of BOK, “there is no point attempting to use 5-FU as an effective chemotherapy treatment," said Puthalakath.

Source: MedicalXpress, July 15, 2019

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