Scientists at ETH Zurich have developed a groundbreaking light-controlled molecular switch that can wake dormant cancer cells from their protective sleep state, making them vulnerable to treatment once again. The research, published in the Proceedings of the National Academy of Sciences, introduces photoswitchable Proteolysis Targeting Chimeras, or photoPROTACs, that selectively degrade glucocorticoid receptors in tumor cells while sparing healthy tissue.
The breakthrough addresses one of the most persistent challenges in cancer treatment: the ability of tumor cells to enter a dormant state that renders them invisible to conventional therapies. In certain forms of lung cancer, stress hormones in the body activate glucocorticoid receptors inside cancer cells, triggering a survival mode in which the cells barely divide. This dormancy allows cancer to persist undetected and later re-emerge aggressively after treatment has concluded.
The research team, led by Katharina Gapp at ETH Zurich and including doctoral student Robin Scheuplein, engineered a novel solution by integrating arylazopyrazole photoswitches into PROTAC molecules. These photoPROTACs activate in the dark and can be reversibly deactivated by ultraviolet light, enabling precise spatial and temporal control over glucocorticoid receptor degradation. The molecular switch is injected directly into the tumor, and light is then applied to deactivate any molecules that migrate into surrounding healthy tissue.
In laboratory cultures of lung cancer cells, the researchers demonstrated that the active substance leads to rapid breakdown of the glucocorticoid receptors, effectively stripping tumor cells of their ability to enter dormancy. The precision of the approach means that healthy cells throughout the body, which also rely on glucocorticoid receptors for essential functions like inflammation control and immune regulation, remain unaffected.
The significance of this work extends beyond lung cancer. The researchers noted that the same photoPROTAC strategy could potentially be adapted to target other hormone receptors implicated in treatment resistance, including the estrogen receptor in hormone-dependent breast cancer and the androgen receptor in advanced prostate cancer. This versatility suggests a broad platform technology for addressing dormancy-driven drug resistance across multiple cancer types.
Experts in the field have described the approach as an elegant solution to the long-standing problem of spatial selectivity in targeted protein degradation. Traditional PROTACs, while highly effective at degrading specific proteins, cannot distinguish between the same receptor in tumor cells versus healthy cells. The addition of a light-controlled on-off mechanism provides a layer of spatial precision that had previously been unachievable with small-molecule therapeutics.
While the research remains in the preclinical stage, the team is now working toward testing the photoPROTAC system in animal models and eventually human clinical trials. The researchers emphasized that combining this technology with existing cancer treatments could provide oncologists with a powerful new tool to prevent tumor recurrence by eliminating the dormant cells that currently escape standard chemotherapy and immunotherapy regimens.
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