Korea University: Development of DNA Damage-Response-Targeting Anticancer Drug for Overcoming Tolerance

Anticancer drug tolerance, an issue commonly encountered in conventional chemotherapy, is caused by the defense mechanisms of cancer cells against drugs. To solve the problem of cancer cell anticancer drug tolerance, responses to DNA damage can be studied, particularly the suppression of DNA damage repair in cancer cells treated with anticancer drugs and the cell cycle checkpoint.
*Cell cycle checkpoint: The cell cycle checkpoint is a step when the cell is monitored in cell cycle regulation. At the checkpoint, damaged DNA is repaired, and if the cell division is inappropriate, the progress of the cell cycle is blocked.

Floxuridine (2′-deoxy-5-fluorouridine or FUDR), an antimetabolic agent of fluoropyrimidine, is a well-known anticancer agent that both suppresses DNA-damage repair and induces DNA damage. However, if a ‘damage-repairing protein’ system defends cancer cells, the effect of anticancer drugs on specific tumors may be inhibited.

When DNA damage occurs in cells, serine/threonine protein phosphatase 2A (PP2A), which is widely distributed in cells and has various functions, mediates cell responses to repair the damage. Furthermore, PP2A has a pivotal role in the repair of the DNA damage in cancer cells caused by chemotherapy or radiotherapy. Therefore, this study suggested a strategy to inhibit the actions of PP2A using a drug delivery system that is activated in a tumor-specific microenvironment.

Professor Jong Seung Kim’s group of the Department of Chemistry at the College of Science found that under a therapy using the FUDR anticancer drug, PP2A induces the ATR-p53-p21-mediated cancer cell repair pathway. Then, the group developed an M1 prodrug molecule by coupling FUDR to a PP2A inhibitor through a disulfide linker, and showed that the prodrug molecule undergoes specific activation in mitochondria and effectively induces cell death in cancer cells by damaging not only their mitochondrial DNA but also their nuclear DNA.

The study was supported by the Leading Researcher Funds from the Ministry of Science and ICT and the National Research Foundation of Korea. The results of the study were published as a front cover article in Angewandte Chemie International Edition (IF=15.34) on March 10, 2022.

Professor Kim commented, “The particular significance of our study is that the results highlight the importance of a DNA-damage response targeting strategy based on a tumor-specific microenvironment activated system. We look forward to seeing a range of progress related to overcoming drug tolerance and conquering the DNA-damage response of cancer cells.”