The prestigious journal "Nature" unveiled findings of scientists from Guangming District in a paper titled "NBS1 lactylation is required for efficient DNA repair and chemotherapy resistance," spearheaded by Professors He Yulong and Zhang Changhua from the Seventh Affiliated Hospital of Sun Yat-sen University.
In a groundbreaking breakthrough, scientists from Guangming District have cracked a century-old mystery that has confounded the global medical community for years. The prestigious journal "Nature" unveiled their findings July 3 in a paper titled "NBS1 lactylation is required for efficient DNA repair and chemotherapy resistance," spearheaded by Professors He Yulong and Zhang Changhua from the Seventh Affiliated Hospital of Sun Yat-sen University.
This research marks a pivotal moment in oncology as it sheds light on the critical regulatory role of lactylation modification in DNA repair proteins, particularly NBS1, emphasizing its significance in tumor chemotherapy resistance. The study not only confirmed this vital mechanism but also proposed innovative methods to combat chemotherapy resistance by targeting NBS1 protein lactylations.
The implications of this discovery are profound. Not only does it elucidate how tumor cells develop resistance to chemotherapy but it also unveils potential avenues for targeted drug interventions that can effectively thwart tumor cell resistance. This breakthrough opens new horizons in tumor immunotherapy, radiation therapy, and tumor recurrence research, promising immense benefits for the countless patients grappling with drug-resistant tumors globally.
Professors Zhang Changhua, Yin Dong, Axel Behrens, and He Yulong are the principal authors of this game-changing publication, with Dr. Chen Hengxing, Dr. Li Yun, and Dr. Li Huafu serving as the co-first authors.
Unraveling the mechanisms of tumor cell drug resistance
The essence of this research lies in demystifying the resilience of tumor cells against chemotherapy, a cornerstone of cancer treatment. By unveiling the intricate interplay between DNA repair mechanisms and chemotherapy resistance, the team at the Guangming hospital pinpointed lactate as a pivotal player in fortifying tumor cell defenses, akin to a shield against drug-induced damage.
This insight allowed them to identify a targeted drug capable of disrupting this resistance mechanism, offering a beacon of hope to patients battling chemotherapy-resistant tumors. With this newfound understanding, the team's work signifies a beacon of hope for future cancer treatments, reinvigorating the efficacy of chemotherapy against resilient tumor cells.
Clinical challenges
Researchers at the hospital, including Professors He Yulong and Zhang Changhua, have been dedicated to studying gastric cancer surgery, both from a fundamental and clinical perspective. Their efforts have led to advanced treatments for gastric cancer, resulting in a five-year survival rate of over 60% for patients with advanced stages of the disease.
The hospital's gastrointestinal surgery team successfully performed a surgery on a young late-stage gastric cancer patient who traveled from Jiamusi, Heilongjiang Province, to seek treatment. Through multidisciplinary discussions and evaluations, the team, with the guidance of Professor He Yulong, cleared the lymph nodes near the affected area, offering hope for the patient's recovery.
The team conducted extensive research and discovered that chemotherapy-resistant patients had higher levels of lactate in their tumor tissues compared to chemotherapy-sensitive patients. This observation led the researchers to explore the role of lactate in tumor survival. They found evidence that lactate could act as an acylation modification donor, affecting the function of substrate proteins.
Motivated by these findings, the team embarked on a four-year research journey with support from various grants and funds.
They discovered that tumor cells convert glucose to lactic acid through glycolysis, enabling them to repair DNA damage more efficiently. This resistance to damage reduces the effectiveness of radiotherapy and chemotherapy.
They identified a drug called Disulfiram that blocks DNA damage repair by inhibiting lactic acid production and the process of lactic acidosis. By disrupting the DNA repair mechanism of tumor cells, Disulfiram renders them sensitive to radiotherapy or chemotherapy once more. This finding has the potential to revolutionize clinical treatments and become an effective anticancer therapy.
As of now, the team has initiated clinical studies and is recruiting patients with peritoneal metastatic cancer who are resistant to conventional treatments. It is expected that this research will soon transition into clinical applications, benefiting a wider population of cancer patients.