Study Discovers How Cancer Evades Chemotherapy, Identifies Mechanism to Reverse

An international team of researchers from the UK and China has uncovered how cancer develops resistance to chemotherapy, addressing one of the most significant challenges in treating this deadly disease.

The early-stage study, conducted using mice and led by The Institute of Cancer Research (ICR) in London and Sun Yat-sen University in China, demonstrated that Stiripentol, a drug currently used to treat epilepsy, can help counteract cancer's resistance to chemotherapy. This discovery could lead to more effective tumor reduction and improved survival rates for cancer patients.

The findings were published in the journal Nature.

Cancer cells exhibit two key characteristics: altered metabolism and genome instability. They change the way they take in and use nutrients to support continuous cell survival. Radiotherapy and most chemotherapy drugs aim to damage DNA, leading to cancer cell death. However, cancer cells must quickly repair this DNA damage to stay alive. Some accumulated metabolites, like 2-hydroxyglutarate, fumarate, and succinate, hinder DNA repair and increase genome instability. However, less is known about metabolites that aid DNA repair. Therefore, understanding how metabolism-driven DNA repair mechanisms support tumour survival is crucial.

In the study, the team focused on lactate, a byproduct that accumulates as cancer cells convert nutrients into energy. They found that lactate was most abundant in chemotherapy-resistant cancer tissues. Researchers examined tissue from 24 patients with stomach cancer, where 15 of the cancers were resistant to chemotherapy and continued to grow.

Using a mouse model, the researchers tested the combination of Stiripentol and chemotherapy. This treatment reduced tumour size for four weeks after treatment and extended survival in mice with stomach cancer to more than 70 days. In contrast, tumours in mice treated with chemotherapy alone shrank for only one week before regrowing, and none of these mice survived longer than 40 days after treatment.

Additionally, lactate was found to alter the structure of a key protein involved in DNA repair, called NBS1, affecting its efficiency.

“Lactate helps protect the genome and allows cancer cells to survive despite the damaging effects of chemotherapy. The findings showed that lactate enhances the DNA repair machinery and contributes to chemotherapy resistance. Chemotherapy is a key treatment for many cancers, but resistance to these drugs leads to many patient deaths. Our study reveals a strong synergy between the LDHA inhibitor stiripentol, a drug already used clinically, and chemotherapy treatments like cisplatin and radiation. This suggests that targeting lactate could be a promising strategy to improve chemotherapy effectiveness and increase survival rates for cancer patients,” said Professor Axel Behrens, Professor of Stem Cell Biology at The Institute of Cancer Research.

Reference: Chen, H., Li, Y., Li, H. et al. NBS1 lactylation is required for efficient DNA repair and chemotherapy resistance. Nature (2024). https://doi.org/10.1038/s41586-024-07620-9