[Health Focus] Discovery of Gene That Neutralizes Targeted Therapy for Breast Cancer

A new factor reducing the effectiveness of mTOR inhibitors, one of the targeted anticancer drugs for breast cancer, has been identified.

Professor Jin-Hyuk Bin of the Department of Biomedical Systems Informatics, Yonsei University College of Medicine, working at Gangnam Severance Hospital (photo), together with a professor from the Netherlands Cancer Institute, published a paper identifying clinically significant resistance factors to the breast cancer treatment mTOR inhibitors.

mTOR (mammalian target of rapamycin) is a protein involved in cell cycle regulation and cell growth. At normal levels, mTOR plays an important role in supporting cell growth and development, but when abnormally activated, it becomes an intracellular cancer signaling pathway that also promotes cancer cell growth. mTOR inhibitors, which apply this mechanism, have characteristics that interfere with cellular signaling and inhibit cell growth. Recently, they have been used as standard treatments for various cancers including breast cancer, kidney cancer, and lung cancer.

However, like other anticancer drugs, mTOR inhibitors have the limitation that cancer cells acquire resistance over long-term administration. When resistance develops, the drug can no longer inhibit cancer cell growth, reducing treatment efficacy. Although many studies have been conducted to elucidate the resistance mechanisms of mTOR inhibitors, these were performed using cell lines that are far removed from the actual human in vivo environment.

The research team conducted resistance studies to mTOR inhibitors in an environment similar to the actual human in vivo environment, where various cells such as immune cells and basal cells exist around cancer cells, through mouse experiments. They induced spontaneous breast cancer in mice by mimicking the actual cancer formation process in humans through genetic mutations. Through this process, they administered mTOR inhibitors long-term to mice with cancer, collected samples during the development of resistance, and tracked changes in the entire genome and proteome using multi-omics research techniques.

During this process, the research team discovered that the MYC gene was specifically amplified only in cancer cells that acquired resistance to mTOR inhibitors, accompanied by various changes related to drug resistance both inside and outside the cancer cells. In particular, it was observed that MYC offsets the main function of mTOR inhibitors, which is the suppression of protein translation, and inhibits the infiltration of immune cells around the cancer cells. Additionally, the team demonstrated through in vitro and animal experiments that the MYC gene actually induces resistance to mTOR inhibitors, and confirmed that this correlation also appears in breast cancer patients who were prescribed mTOR inhibitors.

Professor Jin-Hyuk Bin stated, "Based on quantitative measurements of the MYC gene and protein, it will be possible to predict and select patients who do not respond to mTOR inhibitors, thereby contributing to reducing unnecessary prescriptions."

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