A recent study co-led by a researcher at Fox Chase Cancer Center has identified a key resistance mechanism in breast cancer that could help improve treatment strategies for patients. The research, published in Nature Cancer, examines why some patients with advanced or metastatic HR+/HER2- breast cancer eventually become resistant to CDK4/6 inhibitors, a class of targeted drugs that have improved outcomes for many but are not always effective long-term.
The team found that certain tumors treated with CDK4/6 inhibitors develop an immunosuppressive microenvironment. This environment is made up of cells surrounding the cancer cells and contributes to tumor growth and resistance to therapy. The researchers showed that this immunosuppressive response can be counteracted by using radiation therapy or immune-modulating drugs.
“The takeaway is, let’s give radiotherapy when we can,” said senior author , an Associate Professor in the at Fox Chase. “But when we cannot, now we may have two different alternatives that we can use instead to make these inhibitors better.” Galluzzi conducted the research when he was affiliated with Weill Cornell Medicine in New York before joining Fox Chase last year. Other authors include researchers from Cedars-Sinai Medical Center in Los Angeles.
CDK4/6 inhibitors are typically used alongside hormonal therapy as standard care for patients with advanced HR+/HER2- breast cancer because they target cancer cells more specifically than older chemotherapy drugs.
In mouse models, adding radiation therapy to standard treatment improved effectiveness compared to using CDK4/6 inhibitors and hormonal therapy alone. The researchers observed increased levels of gamma delta T-cells and certain macrophages—both known for suppressing immune responses—in tumors treated only with CDK4/6 inhibitors. Radiation therapy blocked the signaling pathways responsible for raising these cell levels.
“The tumor reacts to CDK4/6 by generating this immunosuppressive microenvironment,” Galluzzi said. “Radiation therapy prevents that from happening.”
Galluzzi also noted that existing drugs targeting gamma delta T cells and immunosuppressive macrophages could offer alternatives for patients who cannot undergo radiation due to factors like multiple tumors or proximity to sensitive organs.
Blood and tissue samples from human patients confirmed the findings: those with higher levels of gamma delta T cells relapsed faster after treatment with CDK4/6 inhibitors than those with normal levels.
“It suggests that what we observe in the mouse also happens in patients,” Galluzzi said. It’s possible that gamma delta T cells could be used as an indicator to help predict which patients will respond better to treatment, he added.
Researchers plan further studies at Fox Chase Cancer Center involving surgical patients treated preoperatively with combinations of CDK4/6 inhibitors and immune-targeting drugs, aiming to observe beneficial changes within tumor samples post-surgery. They hope these investigations will lead toward clinical trials comparing combined therapies against current standard treatments.
Fox Chase Cancer Center is based in Philadelphia, Pennsylvania and was founded in 1904. The center reported over 5,000 surgeries and nearly 3,500 patient admissions during 2022 according to its annual report (https://www.foxchase.org/about-us/history).
