Mass General Brigham Researchers Identify Mutations That Can Lead to Resistance to Some Chemotherapies

Investigators at Mass General Brigham have uncovered how resistance to chemotherapies may occur in some cancers. Researchers focused on a pathway that harnesses reactive oxygen species (ROS) to kill cancer cells. The study found that mutations to VPS35, a key player in this pathway, can prevent chemotherapy-induced cell death. These results, published in Nature, could help pinpoint treatment-resistant tumors.

“ROS play an important role in healthy and diseased cells, but pathways that sense and control cellular ROS levels are not well understood,” said corresponding author Liron Bar-Peled, PhD, of the Krantz Family Center for Cancer Research at Mass General Cancer Center (MGCC), a member of the Mass General Brigham healthcare system. “A clearer understanding of ROS could help us understand why chemoresistance occurs in some cases.”

Low concentrations of ROS are required for normal cell signaling, but higher levels of ROS can damage cells and contribute to diseases such as cancer and neurodegeneration. Researchers know that mitochondria play an important role in ROS production, but it has been unclear if ROS-sensing proteins influence the mitochondria. If they do, this could impact responses to some anti-cancer treatments.

To investigate, co-first authors Junbing Zhang, PhD, Yousuf Ali, PhD, and Harrison Chong, of the Krantz Family Center for Cancer Research, and colleagues screened cancer cells for ROS-sensing proteins that might contribute to chemoresistance. The screen identified mutations that increased treatment resistance, and the team traced two of them to a protein called VPS35. Through further studies, they found that these mutations led to lowered ROS levels within the cell.

In addition, the investigators analyzed VPS35 expression levels in 24 patients with high grade serous ovarian cancer (HGSOC), who received treatment at MGCC. They noted that higher tumoral VPS35 levels were associated with improved treatment responses and with overall survival rates.

Authorship: In addition to Bar-Peled, Zhang, Ali and Chong , Mass General Brigham researchers include Pei-Chieh Tien, Carolina Noble, Tristan Vornbäumen, Andrea C. Noble, Jay Miguel Fonticella, Lina Fellah, Drew Harrison, Stefan Harry, Maolin Ge, Neha Khandelwal, Yingfei Huang, Maëva Chauvin, Anica Tamara Bischof, Grace Marie Hambelton, Magdy Farag Gohar, Siwen Zhang, Sara Bouberhan, Esther Oliva, Mari Mino-Kenudson, Michael Lawrence, Justin F Gainor, Nabeel Bardeesy, Raul Mostolavsky, David Pépin, and Christopher Ott. Additional authors include James Woods, Zehra Ordulu, Anthony P Possemato, MinGyu Choi, Natalya N Pavlova, Sean A Beausoleil, and Brian Liau.

Disclosures: Bar-Peled is a founder, consultant and holds privately held equity in Scorpion Therapeutics. Multiple co-authors are employees of Cell Signaling Technology. Liau is a founder, member of the scientific advisory board, and equity holder in Light Horse Therapeutics.

Funding: This work was supported by the Damon Runyon Cancer Research Foundation (62-20), the American Association for Cancer Research (19-20-45-BARP), the American Cancer Society, The Krantz Family Center for Cancer Research Quantum Award (to L-B.P, M.L and C.O), FujiFilm Therapeutics Graduate Program Fellowship (J.W.), 412 post-baccalaureate fellowship from the UMass Boston-DF/HCC Partnership to Advance Cancer Health Equity (NIH/NCI U54CA156734 (J.M.F) the Melanoma Research Alliance, the Ludwig Cancer Center of Harvard Medical School, Lungevity, ALK Positive, V-Foundation, Mary Kay Foundation, Paula and Rodger Riney Foundation, the PEW-Stewart Trusts, Lisa and Mark Schwartz and the NIH/NCI (1DP2GM137494, R35GM153476 to B.L. 1R21CA226082-01, R37CA260062 to L.B-P) DF/HCC SPORE in Gastrointestinal Cancer, NIH/NCI (P50CA127003).

Paper cited: Zhang J et al. “Oxidation of Retromer Complex controls Mitochondrial Translation” Nature DOI: 10.1038/s41586-025-08756-y