There are a number of phosphatidylinositol 3-kinase inhibitors (PI3K inhibitors) in the clinic to treat various cancers by curbing the function of this class of enzymes. Now, instead of focusing on the enzyme, Harvard researchers have highlighted glutathione, a byproduct of abnormal PI3K signaling, as a potential new target in breast cancer.
The team, led by investigators at Beth Israel Deaconess Medical Center, a Harvard affiliate, found that in breast cancer cells, abnormal signaling through the PI3K/AKT pathways causes the production of glutathione, a cellular antioxidant. This helps prevent damage to cellular components and can help cancer cells survive chemotherapy.
They tested a combination of standard chemotherapy with a drug that inhibits glutathione production in lab dishes and mice. The combo caused “significant regression” of breast cancer with PI3K/AKT mutations.
“Our work has uncovered a vulnerability in human breast cancer that is used by tumor cells to escape the lethal effects of conventional chemotherapy and that leads to resistance to such therapies,” said Alex Toker, chief of the Division of Signal Transduction in the Departments of Medicine and Pathology and the Cancer Center at BIDMC. His team hopes to target this vulnerability with a one-two punch of chemo and a glutathione blocker, to potentially improve therapeutic outcomes and reduce toxicity in cancer treatment.
While the team didn’t specifically investigate them in the study, targeting glutathione could be applicable in aggressive and treatment-resistant HER2-positive breast cancer. Toker said the PI3K/AKT pathway is “frequently aberrantly activated” in this type of cancer. Gilead’s ($GILD) Zydelig is the first and currently the only approved PI3K inhibitor. It treats leukemia and two types of lymphoma in patients who have already received two systemic therapies.
However, Toker’s team still has some questions to answer before their drug can be tested in humans. They are uncertain if a specific glutathione inhibitor can be developed for safe use in humans. Further research is needed to identify any other antioxidants in tumor cells that the PI3K/AKT pathway can leverage to drive cancer, and to determine if glutathione production occurs in tumors that do not have the PI3K/AKT pathway mutation.
Image Courtesy of National Cancer Institute