- Korea Research Institute of Bioscience and Biotechnology proposes new colorectal cancer treatment strategy

- Key cause of resistance to anticancer drug 5-FU identified

- Findings suggest possibility of restoring effectiveness of existing chemotherapy

Researchers at the Korea Research Institute of Bioscience and Biotechnology analyze the properties of the anticancer drug 5-FU. [Provided by Korea Research Institute of Bioscience and Biotechnology]
Researchers at the Korea Research Institute of Bioscience and Biotechnology analyze the properties of the anticancer drug 5-FU. [Provided by Korea Research Institute of Bioscience and Biotechnology]

South Korean researchers have identified the key mechanism by which colorectal cancer cells develop resistance to a widely used anticancer drug.

A research team led by Dr. Cho Hyun-su of the Stem Cell Convergence Research Center at the Korea Research Institute of Bioscience and Biotechnology, working jointly with a team led by Professor Heo Geun of Kyungpook National University, announced Thursday they had pinpointed the core cause of colorectal cancer cells developing resistance to the anticancer drug 5-FU and proposed a new treatment strategy to restore the cells' sensitivity to the drug.

While the overall incidence of colorectal cancer is declining, rates among people under 50 are rising.

5-FU is one of the most widely used anticancer drugs, employed in the treatment of colorectal, stomach, breast and pancreatic cancers, among others. It works by blocking the production of nucleotides needed for normal DNA and RNA synthesis and by inserting incorrect bases into DNA, thereby suppressing cancer cell division and proliferation. A major limitation, however, is that cancer cells can acquire resistance with repeated administration, causing the drug to lose its effectiveness.

The research team created drug-resistant colorectal cancer cells by repeatedly exposing them to 5-FU, then conducted a detailed analysis comparing them with ordinary cancer cells.

As a result, the activity of a protein called EHMT2 was found to be significantly elevated in the resistant cancer cells. EHMT2 regulates the activity of specific genes within cells, and the team identified it as a potential key factor in anticancer drug resistance.

Analysis of patient data also confirmed a trend in which patients with higher EHMT2 activity showed lower responses to 5-FU treatment and reduced survival rates.

The team also investigated whether inhibiting EHMT2 function could restore the sensitivity of resistant cancer cells to the drug.

In experiments, reducing EHMT2 activity caused cancer cells that had previously survived 5-FU exposure to begin dying again, with proliferation also declining sharply. Conversely, artificially increasing EHMT2 levels in ordinary cancer cells strengthened their resistance to the drug.

The findings demonstrate that EHMT2 plays a central role in inducing anticancer drug resistance and that inhibiting it can return cancer cells to a treatable state.

The research team led by Dr. Cho Hyun-su (center) of the Korea Research Institute of Bioscience and Biotechnology. [Provided by Korea Research Institute of Bioscience and Biotechnology]
The research team led by Dr. Cho Hyun-su (center) of the Korea Research Institute of Bioscience and Biotechnology. [Provided by Korea Research Institute of Bioscience and Biotechnology]

To verify whether the treatment strategy would also prove effective in real patient environments, the team conducted additional validation using patient-derived organoids and animal models.

When 5-FU and an EHMT2 inhibitor were administered together, the growth of resistant colorectal cancer that had previously shown no response was markedly reduced.

The results suggest it may be possible to enhance the effectiveness of existing chemotherapy by lowering cancer cells' resistance — without developing a new anticancer drug — pointing to the potential for a new treatment strategy to overcome drug resistance.

"Since 5-FU is used to treat not only colorectal cancer but also stomach, pancreatic, breast and head and neck cancers, this approach could be broadly applied to overcoming anticancer drug resistance across multiple cancer types," Dr. Cho said.

The research was published in Signal Transduction and Targeted Therapy, an international journal in the field of basic medicine.


nbgkoo@heraldcorp.com