PHILADELPHIA — Targeted cancer drugs known as CDK4/6 inhibitors have shown promise in treating advanced or metastatic HR+/HER2- breast cancer, yet resistance remains a challenge. Recent research led by a Fox Chase Cancer Center scientist sheds light on the mechanisms behind this resistance and proposes three strategies to enhance treatment efficacy.
Published in Nature Cancer, the study reveals how tumors can form an immunosuppressive microenvironment in response to CDK4/6 inhibitors, increasing resistance. This environment consists of cells surrounding the cancer cells that are crucial for tumor growth. The research suggests that radiation therapy or immune-modulating drugs could mitigate this effect.
“The takeaway is, let’s give radiotherapy when we can,” said senior author , an Associate Professor 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 while affiliated with Weill Cornell Medicine before joining Fox Chase last year. Other contributors include researchers from Cedars-Sinai Medical Center.
CDK4/6 inhibitors target cancer cells more precisely than older chemotherapy drugs and are typically used with hormonal therapy for HR+/HER2- breast cancer patients as standard care.
The study demonstrated in a mouse model that combining radiation therapy with CDK4/6 inhibitors and hormonal therapy was more effective than standard care alone. Researchers found elevated levels of gamma delta T-cells and macrophages suppressing immune responses in some tumors treated with CDK4/6 inhibitors. Radiation therapy was shown to block pathways increasing these cells.
“The tumor reacts to CDK4/6 by generating this immunosuppressive microenvironment,” Galluzzi explained. “Radiation therapy prevents that from happening.”
Galluzzi also noted existing drugs targeting gamma delta T-cells and macrophages offer alternative approaches for patients unable to undergo radiation due to multiple tumors or proximity to sensitive organs.
Researchers confirmed through human blood and tissue samples that high levels of gamma delta T-cells correlated with faster relapse rates compared to normal levels. “It suggests that what we observe in the mouse also happens in patients,” Galluzzi stated, indicating potential predictive value for patient responses.
Future studies will involve treating HR+/HER2- breast cancer patients at Fox Chase with combined therapies targeting gamma delta T-cells or macrophages before surgery, examining post-surgical tumor changes. A clinical trial is planned to assess if combined therapies surpass standard care effectiveness.
The study was published in Nature Cancer.
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