Chinese researchers have solved a longstanding puzzle in the field of oncology, with the results being published by Nature on July 3, Beijing time. The study, led by Professors He Yulong and Zhang Changhua from the Seventh Affiliated Hospital of Sun Yat-sen University, reveals the critical role of NBS1 lactylation in efficient DNA repair and chemotherapy resistance.

This research not only confirms the involvement of NBS1 lactylation in tumor chemotherapy resistance but also proposes innovative strategies to reverse drug resistance by targeting and inhibiting NBS1 lactylation or regulating lactate metabolism pathways.

The research results were published in Nature.

This discovery marks a significant breakthrough in global cancer research. It not only elucidates how tumor cells resist chemotherapy but also identifies targeted therapies to combat drug resistance, offering new perspectives on issues including tumor immunotherapy, radiotherapy, and cancer recurrence.

Chemotherapy and radiotherapy are pivotal in cancer treatment, inducing DNA double-strand breaks in tumor cells that, when irreparably damaged, lead to cell death. Understanding and disrupting the mechanisms behind tumor drug resistance is a crucial step towards enhancing the efficacy of cancer therapies.

The Warburg effect, first proposed by Otto Warburg in 1923, describes how tumor cells metabolize glucose primarily via glycolysis, even in the presence of oxygen, leading to the production of lactate. This metabolic phenomenon has long puzzled scientists: why do cancer cells opt for a high-energy-consuming, low-efficient metabolic pathway?

Dr. Hengxing Chen, a key contributor to the study, highlighted the challenges faced during their research journey. "Exploring the role of lactate in cancer metabolism was uncharted territory," said Dr. Chen. "Many experiments were pioneering, lacking precedents, which pushed us to innovate new methods such as chemical cross-linking mass spectrometry."

Over four years of investigation, Professors He and Zhang's team made several groundbreaking discoveries. They uncovered the role of the Warburg effect in promoting tumor growth and resilience against external damage. Furthermore, they identified a targeted drug, stiripentol, capable of combating the Warburg effect by inhibiting lactate production and lactylation, thereby disrupting DNA repair mechanisms in tumor cells and restoring their sensitivity to chemotherapy.

Professors Yulong He (Right) and Changhua Zhang (Middle) in operation

"For more than 100 years, scientists have been discussing the mystery of the Warburg effect, but it has never been clarified. Our study has revealed the answer: tumor cells produce lactate to lactylates NBS1, thereby quickly repairing the broken double strands of tumor cell DNA and promoting self-repair and survival," Professor Changhua Zhang said. "The century-old mystery has finally found its answer."

The safety profile of stiripentol in clinical settings, previously used to treat childhood epilepsy, supports its potential repurposing as a novel cancer treatment. Clinical trials targeting critically ill peritoneal metastatic cancer patients, resistant to conventional therapies, have already commenced, promising translation of these findings into clinical applications and potentially benefiting cancer patients worldwide.

Link to the paper:https://www.nature.com/articles/s41586-024-07620-9

Link to the report:https://www.newsgd.com/node_5c070fdd03/f2abb41971.shtml