Researchers at Mass General Brigham have made a significant stride in understanding how some cancers develop resistance to chemotherapy. Their work focuses on the role of reactive oxygen species (ROS) in killing cancer cells and how this process can be disrupted. The study, published in Nature, reveals that mutations in the VPS35 protein, a key component of the ROS pathway, can prevent chemotherapy-induced cell death, potentially leading to treatment failure. Liron Bar-Peled, PhD, from the Krantz Family Center for Cancer Research at Mass General Cancer Center (MGCC), emphasized the importance of ROS in both healthy and diseased cells. He noted that the mechanisms controlling cellular ROS levels are not fully understood, and a clearer understanding could provide insights into chemoresistance. While low concentrations of ROS are essential for normal cell signaling, elevated levels can cause cellular damage and contribute to diseases like cancer and neurodegeneration. The research team investigated the role of ROS-sensing proteins and their potential influence on mitochondria, the cell's powerhouses responsible for ROS production. Understanding this connection is crucial, as it could significantly impact how cancer cells respond to anti-cancer treatments. To identify potential contributors to chemoresistance, the researchers screened cancer cells for ROS-sensing proteins. This screening process led to the identification of mutations that increased treatment resistance, with two of these mutations traced back to the VPS35 protein. Further investigation revealed that these VPS35 mutations resulted in reduced ROS levels within the cancer cells, effectively shielding them from the cytotoxic effects of chemotherapy. To validate these findings, the researchers analyzed VPS35 expression levels in 24 patients with high-grade serous ovarian cancer (HGSOC) treated at MGCC. The results showed a strong correlation between higher tumoral VPS35 levels and improved treatment responses, as well as increased overall survival rates. This suggests that VPS35 could serve as a potential biomarker for predicting treatment outcomes in HGSOC. These findings offer a promising avenue for developing strategies to overcome chemoresistance in cancer treatment. By targeting the VPS35 protein or modulating ROS levels within cancer cells, it may be possible to enhance the effectiveness of chemotherapy and improve patient outcomes. Future research will focus on further elucidating the mechanisms by which VPS35 regulates ROS levels and exploring potential therapeutic interventions.
