Study Reveals Mechanism Behind Chemotherapy Resistance in Certain Cancers

New Delhi: In a major breakthrough that could aid in identifying treatment-resistant cancers, researchers in the US have discovered how certain tumors manage to evade the effects of chemotherapy. The study, conducted by scientists from Mass General Brigham and published in Nature, sheds light on a key mechanism driving chemoresistance.

Chemotherapy resistance, where cancer cells cease responding to treatment, remains a major obstacle in oncology. It often leads to disease recurrence and poor prognosis. The new research focuses on how cancer cells manage oxidative stress — a process involving reactive oxygen species (ROS) — and how this influences their sensitivity to chemotherapy.

ROS are molecules that play a dual role in cells — at low levels, they assist in normal cellular functions, while at higher concentrations, they can damage cells and are commonly used by chemotherapies to kill cancer cells. The study found that a gene called VPS35, which is involved in controlling ROS levels, plays a critical role in determining how cancer cells respond to chemotherapy.

“Our understanding of ROS-regulating pathways is still emerging,” said senior author Dr. Liron Bar-Peled of the Krantz Family Center for Cancer Research. “This insight helps explain why some tumours don’t respond to treatment.”

Using a broad screening approach, the researchers identified mutations in ROS-sensing proteins that were linked to resistance. Specifically, mutations in VPS35 were found to reduce intracellular ROS levels, making chemotherapy less effective. These mutations appear to interfere with the mitochondria’s ability to generate ROS, blunting the treatment’s intended effect.

To validate their findings, the team analysed tumour samples from 24 patients with high-grade serous ovarian cancer treated at Mass General Cancer Center. Patients with higher levels of VPS35 expression in their tumours showed better responses to chemotherapy and improved overall survival, highlighting the potential of VPS35 as a biomarker for treatment outcomes.

The findings could open doors to more targeted therapies and help clinicians predict which patients are more likely to benefit from chemotherapy.