Pharmacological Modulation of DNA Damage Response Pathways in Cancer Therapy

Abstract

When DNA is damaged, cells activate the DNA Damage Response (DDR), a protective mechanism that prevents harmful mutations and chromosomal changes that can lead to cancer. DDR coordinates DNA repair with cell cycle control, ensuring that cells do not divide with damaged genetic material [1]. It evolved to protect organisms from both internal and external DNA-damaging agents. Interestingly, many cancer therapies such as radiation and chemotherapy work by damaging DNA, making DDR a key factor in treatment resistance[2] Radiotherapy, used in about 50% of cancer cases, relies on causing DNA damage to kill tumor cells. A specific type of injury caused by radiation is complex DNA damage (CDD), where multiple lesions occur close together on the DNA helix. CDD is particularly toxic because it is difficult for the cell to repair. The severity of CDD increases with higher linear energy transfer (LET), meaning that high-LET radiation (like carbon ions) causes more damage than low-LET radiation (like X-rays) [3]. However, this can also increase the risk of harming healthy tissue. Recent research focuses on developing DDR inhibitors that block repair in cancer cells, making them more sensitive to treatment. Several of these drugs are in preclinical and clinical testing, both alone and in combination with other therapies[4].