Key Protein Behind Chemotherapy Resistance in Colorectal Cancer Identified

President Kwon Suk-yoon of the Korea Research Institute of Bioscience and Biotechnology (KRIBB).

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 Hur Keun 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 non-resistant cancer cells.

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 datasets 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.

A diagram of identifying a key mechanism underlying 5-FU resistance in colorectal cancer and proposing a new therapeutic strategy to restore tumor sensitivity to treatment.

In contrast, artificially increasing EHMT2 expression in non-resistant 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. Cho Hyun-Soo, 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.”

The study was published online on May 18 in Signal Transduction and Targeted Therapy (Impact Factor: 52.7), one of the world’s leading journals in translational medicine and targeted therapeutics.

The article is titled “Targeting EHMT2 overcomes 5-fluorouracil resistance in colorectal cancer by modulating cell cycle and apoptosis.”

The corresponding authors are Hur Keun of Kyungpook National University and Han Tae-Su, Kim Dae-Soo, Son Mi-Young, and Cho Hyun-Soo of the Korea Research Institute of Bioscience and Biotechnology (KRIBB).

The first author is In Hwan-tae of KRIBB.

This research was supported by the Major Research Programs of KRIBB, the KRIBB Strategic Research Program, and the Bio and Medical Technology Development Program of the Ministry of Science and ICT.

Dr. Son Mi-young and Dr. Cho Hyun-soo Cho at the Stem Cell Convergence Research Center of the KRIBB. (Photos: KRIBB)

KRIBB Transfers Human Intestinal Organoid Technology to Accelerate Regenerative Therapy Development

The Korea Research Institute of Bioscience and Biotechnology (KRIBB) has transferred a proprietary human intestinal organoid technology to a biotechnology company, marking a significant step toward the commercialization of regenerative therapies for difficult-to-treat intestinal diseases.

KRIBB announced that a research team led by Dr. Son Mi-Young has licensed its core technology platform for human intestinal organoid-based regenerative therapeutics and drug evaluation to Organoid Sciences Co., Ltd., a company specializing in organoid-based regenerative medicine.

The agreement includes an exclusive license valued at approximately KRW 8.3 billion, consisting of upfront and milestone payments, as well as future royalty payments based on commercial sales.

The licensed technology package incorporates three key patents and accumulated know-how developed since 2018, when Dr. Son’s team first established a method for generating mature intestinal organoids derived from human pluripotent stem cells.

To facilitate clinical translation beyond laboratory research, the team has integrated multiple technologies into a single platform, including:

The core innovation enables the generation of mature intestinal organoids that closely resemble the structure and function of the human intestine.

These organoids can be utilized both as regenerative therapeutics and as advanced platforms for drug evaluation.

The technology also addresses several long-standing challenges associated with organoid-based therapies, including consistency, reproducibility, and large-scale supply.

By incorporating cryopreservation and mass-production technologies, the platform provides a foundation for developing off-the-shelf cell therapies that can be readily available when needed.

Unlike conventional treatments that primarily focus on controlling inflammation, intestinal organoid therapies aim to regenerate damaged tissue directly.

As a result, the technology is expected to contribute to the development of new treatments for refractory intestinal disorders, including inflammatory bowel disease and radiation-induced enteritis.

Organoid Sciences plans to utilize the licensed technology to accelerate the development of regenerative therapies for intestinal diseases while also expanding its application to New Approach Methodologies (NAMs) for drug efficacy and toxicity assessment.

The platform is expected to support the development of more human-relevant testing systems that can reduce reliance on animal experiments and improve the predictive accuracy of preclinical drug evaluation.

This technology transfer is particularly significant because it demonstrates how foundational organoid research developed in a public research institute can be combined with industrial expertise in clinical development and commercialization to advance actual therapeutic products.

KRIBB also plans to support the establishment of organoid GMP manufacturing, quality evaluation, and preclinical validation systems to facilitate the development of clinically applicable regenerative medicines.

Future research efforts will expand toward the development of larger-scale artificial organs.

“This technology transfer represents an important milestone in translating KRIBB’s human intestinal organoid technologies into practical therapeutic applications,” said Dr. Son Mi-Young, principal investigator of the study.

“We will continue our efforts to develop regenerative therapies that can provide meaningful benefits to patients suffering from refractory intestinal diseases.”

“This agreement is a representative example of how KRIBB’s long-standing investments in organoid research can lead to real-world therapeutic development and commercialization through collaboration with industry,” said Dr. Kwon Seok-Yoon, President of KRIBB.

“KRIBB will continue to contribute to public health and national bioinnovation by advancing world-class technologies and promoting their successful translation into industrial applications.”