Even after patients with cancer have been successfully treated, the risk of relapse continues to loom over them for years or even decades. One explanation is that cancer cells enter a dormant state, where they are nonproliferating and drug-resistant. Reactivation of these dormant cancer cells then leads to disease relapse.
Now, researchers from ETH Zurich in Switzerland have developed a light-responsive molecular switch that targets a central driver of dormancy in lung cancer (Proc. Natl. Acad. Sci., doi: 10.1073/pnas.2528760123). The tool showed promising in vitro performance, reversing dormancy in cancer cells and highlighting its potential as a therapeutic agent against cancer resistance mechanisms.
“While the current study focuses on non-small-cell lung cancer, the modular nature of the system means it can in principle be adapted to degrade other nuclear receptors relevant in oncology,” said Robin Scheuplein, a doctoral student in the research group led by Katharina Gapp at ETH Zurich. “We see the platform as broadly applicable wherever a receptor of interest can be engaged by an appropriate targeting ligand.”
Switching off receptors
In the current work, Scheuplein, Gapp and their colleagues had their sights set on the glucocorticoid receptor (GR), one of the key stress hormone receptors. In some types of cancer, dormancy is triggered by stress hormones that are recognized by GRs.
“Glucocorticoids play a critical role in driving cancer cell dormancy in nonsmall-cell lung cancer, and while eliminating GR activity in tumor cells is a therapeutically attractive idea, systemic GR degradation throughout the body would interfere with its many essential biological functions,” Scheuplein said. “We therefore set out to create a system that could restrict GR degradation precisely to the tumor site, using light as the controlling element.”
They integrated photoswitchable elements into Proteolysis Targeting Chimeras (PROTACs), a class of molecules that degrades proteins with high specificity and efficacy, to create light-responsive PROTACs (photoPROTACs). Their PhotoPROTACs featuring arylazopyrazole photoswitches—which uniquely activate in the dark and are reversibly inactivated by UV light—enabled potent, spatiotemporally controlled GR degradation.
Next steps
After achieving rapid GR degradation and dormancy reversal in lung cancer cell cultures, the researchers now plan to test photoPROTACs in more complex systems, such as organoid models. They also wish to explore other targets besides GR, such as estrogen receptor alpha, which is central to hormone-dependent breast cancer, and the androgen receptor, a key driver of advanced prostate cancer.
“In parallel, the system needs to be adjusted to respond to longer wavelengths, since near-infrared light penetrates tissue more deeply and gently, which will be essential for reaching deeper-seated tumors beyond what an endoscope can address for lung cancer,” said Gapp.