A research team led by Dr. Hyun-Soo Cho at the Stem Cell Convergence Research Center of the Korea Research Institute of Bioscience and Biotechnology, along with Professor Geun Heo of Kyungpook National University, announced on June 9 that they have identified a key mechanism behind resistance to 5-fluorouracil (5-FU) in colorectal cancer. The study proposes a new therapeutic strategy to restore tumor sensitivity to this widely used chemotherapy drug.
The researchers generated colorectal cancer cells resistant to repeated 5-FU exposure and compared them with non-resistant cells. Their analysis found increased activity of EHMT2, a protein involved in regulating gene expression through epigenetic mechanisms. Analysis of patient datasets showed that those with higher EHMT2 activity had poorer responses to 5-FU treatment and lower overall survival rates.
When the team inhibited EHMT2 activity, previously resistant cancer cells regained sensitivity to 5-FU, resulting in increased cell death and reduced tumor proliferation. Conversely, increasing EHMT2 expression made non-resistant cells more resistant to chemotherapy. The findings indicate that targeting EHMT2 may help reverse chemotherapy resistance.
Further validation was conducted using patient-derived colorectal cancer organoids and animal models. Combining 5-FU with an EHMT2 inhibitor significantly suppressed the growth of previously treatment-resistant tumors. The researchers say this approach could improve existing therapies without requiring entirely new anticancer drugs by reducing cellular resistance.
The study highlights a previously unrecognized mechanism for how cancer cells adapt to chemotherapy and identifies EHMT2 as a promising target for reversing this process. According to the article, these results may also apply beyond colorectal cancer, potentially benefiting patients with gastric, pancreatic, or breast cancers treated with 5-FU.
The research was supported by programs from KRIBB and South Korea's Ministry of Science and ICT. The findings were published online on May 18 in Signal Transduction and Targeted Therapy under the title "Targeting EHMT2 overcomes 5-fluorouracil resistance in colorectal cancer by modulating cell cycle and apoptosis."
