Novel Mechanism Discovered in Cellular Resistance to Anticancer Drugs

Scientists from Tokyo Metropolitan University have identified a new pathway through which cells can withstand the effects of alovudine, a vital antiviral and anticancer medication. Their research, recently published in the journal Nucleic Acids Research, sheds light on the role of DNA repair proteins in drug resistance.

The study highlights the protein flap endonuclease-1 (Fen1), which enhances cell survival by counteracting the toxic buildup of another protein, 53BP1. This discovery underscores the underestimated importance of Fen1 in cancer treatment strategies. Importantly, it may serve as both a target for new therapies and a biomarker for evaluating treatment efficacy.

Chain-terminating nucleoside analogs (CTNAs), molecules that mimic DNA nucleosides, have been used since the 1980s for antiviral and cancer therapies. Their effectiveness stems from their ability to interfere with DNA replication, a process that is hyperactive in infected or cancerous cells, leading to inhibited growth. Despite this, healthy cells exhibit mechanisms to resist CTNA toxicity, limiting their therapeutic potential.

Alovudine, containing fluorine, was initially explored as an HIV treatment. However, clinical trials were halted in phase II due to toxicity concerns. Researchers, led by Professor Kouji Hirota, have been investigating how normal cells resist CTNA effects. Prior work revealed that BRCA1, a key DNA repair protein involved in homologous recombination, played a significant role in mediating resistance.

Building on that, the team examined Fen1, which is responsible for removing short single-stranded DNA sections called Okazaki fragments during DNA replication. Their experiments using genetically modified chicken cells demonstrated that when Fen1 activity is suppressed, cells become highly vulnerable to alovudine, with a marked reduction in replication speed.

Interestingly, the absence of 53BP1, a protein that congregates at DNA nicks, was found to restore tolerance to alovudine in Fen1-deficient cells. This suggests that the accumulation of 53BP1 at long DNA flaps impedes DNA repair efforts, halting replication. Therefore, Fen1 appears integral in preventing this buildup, facilitating DNA repair and cell survival.

Further investigations showed that disrupting Fen1 and BRCA1 independently decreases drug resistance. When both pathways are inhibited, cells are even more susceptible to alovudine. This indicates that Fen1's role in drug tolerance functions separately from BRCA1's known DNA repair functions.

Understanding how cells evade the toxicity of chain-terminating nucleosides could lead to innovative treatments, particularly for tumors deficient in Fen1. Additionally, Fen1 levels might predict how well a tumor responds to certain drugs, aiding personalized medicine. The research team plans to extend their work to human cell models and explore applications across various cancer types, including solid tumors.

Source: MedicalXpress