A team of South Korean researchers has uncovered a hidden mechanism that may explain why one of the world's most widely used colorectal cancer drugs gradually stops working in many patients, raising hopes for a new strategy to make existing treatments effective again.

The discovery centres on a protein called EHMT2, which appears to help cancer cells adapt and survive repeated attacks from 5-fluorouracil (5-FU), a chemotherapy medicine that has been a cornerstone of colorectal cancer treatment for decades. Colorectal cancer is one of the most common cancers worldwide, and while many patients initially respond well to treatment, it often returns after tumours develop resistance to chemotherapy.

The study was led by Dr Hyun-Soo Cho of the Korea Research Institute of Bioscience and Biotechnology (KRIBB)'s Stem Cell Convergence Research Center in collaboration with Professor Geun Heo of Kyungpook National University.

To understand how resistance develops, researchers spent months repeatedly exposing colorectal cancer cells to 5-FU in laboratory experiments until a population of drug-resistant cells emerged. They then compared these cells with treatment-sensitive cancer cells. What stood out was a sharp rise in the activity of EHMT2, a protein that controls how genes are switched on and off through a process known as epigenetics. In simple terms, epigenetics acts like a set of instructions that tells cells which genes to use without changing the DNA itself.

The findings were even more striking when the team analysed patient datasets. Patients with higher EHMT2 activity tended to respond poorly to 5-FU treatment and had lower survival rates than those with lower activity levels.

The researchers then tested whether blocking EHMT2 could reverse the problem. The results were encouraging. Resistant cancer cells regained sensitivity to 5-FU, leading to greater cancer cell death and slower tumour growth. Meanwhile, artificially increasing EHMT2 levels made previously responsive cancer cells harder to kill.

To move beyond the laboratory bench, the team examined patient-derived organoids—tiny three-dimensional tumour models grown from patients' own cancer tissue—and animal models. When 5-FU was combined with an EHMT2 inhibitor, the growth of resistant tumours fell significantly.

Cancer specialists have long regarded drug resistance as one of the most stubborn barriers in oncology. Previous studies have explored genetic mutations, tumour microenvironments and immune-related pathways as possible drivers of resistance. The new research contributes significantly to our understanding of drug resistance by identifying an epigenetic mechanism that seems to assist tumours in evading treatment.

“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.”

Experts caution that the findings are still at the preclinical stage and must be confirmed in human trials. Yet the implications could be far-reaching. Because 5-FU is also commonly used against stomach, pancreatic and breast cancers, a successful strategy to block EHMT2 could potentially benefit patients across several cancer types.

Rather than replacing existing medicines, the research points to a simpler and potentially powerful idea: helping trusted cancer drugs work again when tumours have learned to resist them.