Key protein behind chemotherapy resistance in colorectal cancer identified

One of the most widely used chemotherapeutic agents for colorectal cancer is 5-fluorouracil (5-FU), a cornerstone treatment that has improved outcomes for countless patients. However, repeated treatment often leads to drug resistance, allowing cancer cells to adapt and gradually evade the effects of therapy.

In many patients, tumors initially respond well to treatment but later acquire resistance, ultimately resulting in treatment failure and disease recurrence. Despite its clinical importance, the molecular mechanisms that enable cancer cells to withstand 5-FU therapy have remained poorly understood.

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 (KRIBB), in collaboration with Professor Geun Heo of Kyungpook National University, has identified a key mechanism underlying 5-FU resistance in colorectal cancer and proposed a new therapeutic strategy to restore tumor sensitivity to treatment.

To investigate how resistance develops, the researchers generated colorectal cancer cells that survived repeated exposure to 5-FU and compared them with nonresistant cancer cells. The paper is published in the journal Signal Transduction and Targeted Therapy.

Their analysis revealed a marked increase in the activity of EHMT2, a protein involved in regulating gene expression through epigenetic mechanisms. The team hypothesized that EHMT2 could play a central role in chemotherapy resistance.

Analysis of patient data sets supported this conclusion. Patients with elevated EHMT2 activity showed poorer responses to 5-FU treatment and lower overall survival rates, indicating a strong association between EHMT2 activation and unfavorable clinical outcomes.

The researchers next investigated whether suppressing EHMT2 could reverse resistance. When EHMT2 activity was inhibited, previously resistant cancer cells regained sensitivity to 5-FU, leading to increased cancer cell death and significantly reduced tumor cell proliferation. In contrast, artificially increasing EHMT2 expression in nonresistant cells enhanced their resistance to chemotherapy.

These findings demonstrate that EHMT2 functions as a critical regulator of chemotherapy resistance and that targeting this protein can potentially return resistant cancer cells to a treatment-responsive state.

To determine whether this strategy would also be effective in clinically relevant settings, the team conducted additional validation studies using patient-derived colorectal cancer organoids and animal models. When 5-FU was combined with an EHMT2 inhibitor, the growth of previously treatment-resistant colorectal tumors was significantly suppressed.

The results suggest that improving the effectiveness of existing therapies may be possible without developing entirely new anticancer drugs. Instead, reducing cancer cell resistance could restore the therapeutic benefits of established treatments and provide a new strategy for overcoming chemotherapy resistance.

The study is significant because it reveals a previously unrecognized mechanism by which cancer cells adapt to chemotherapy and identifies a promising therapeutic target capable of reversing that process. The findings may have implications beyond colorectal cancer, potentially extending to other cancers commonly treated with 5-FU, including gastric, pancreatic and breast cancers.

“This study demonstrates that the epigenetic regulatory protein EHMT2 plays a critical role in the process by which cancer cells adapt to chemotherapy,” said Dr. Hyun-Soo Cho, the study’s lead investigator.

“Targeting EHMT2 may provide a new therapeutic approach to overcoming drug resistance and enhancing the efficacy of existing anticancer treatments.”

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Sadie Harley

BSc Life Sciences & Ecology. Microbiology lab background with pharmaceutical news experience in oil, gas, and renewable industries.

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Andrew Zinin

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