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Transcriptomic profiling of A549 cells in response to dexamethasone, in the context of light-controlled GR degradation using novel GR-PhotoPROTACs

ABSTRACT: Glucocorticoid receptor (GR) signaling, activated by dexamethasone (Dex), induces a reversible dormancy state in non-small cell lung cancer (NSCLC) cells, contributing to therapy resistance. To enable precise modulation of GR activity, we developed photoswitchable PROTACs (PhotoPROTACs) incorporating arylazopyrazole scaffolds that allow reversible, wavelength-specific control of GR degradation. A549 lung carcinoma cells were incubated with the active (E-isomer) or inactive (Z-isomer) form of PhotoPROTAC KH-5-309 or KH-5-306 for 12 hours, with Dex added during the final 2 hours. RNA sequencing revealed that the E-isomer of KH-5-309 selectively disrupts GR-driven dormancy-associated gene expression, while the Z-isomer remains functionally inert. This dataset provides a resource for understanding GR-mediated dormancy and demonstrates the utility of light-responsive chemical tools for spatiotemporal control of stress hormone receptor signaling to disrupt cancer cell dormancy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE304966 | GEO | 2026/05/21

REPOSITORIES: GEO

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Light-Controlled Disruption of Cancer Cell Dormancy via Photoswitchable Stress Hormone Receptor Degraders

Project description:Cancer cell dormancy is a key contributor to therapy resistance and disease relapse. The glucocorticoid receptor (GR), a major mediator of stress hormone signaling, has emerged as a central regulator of dormancy in non-lymphoid solid tumors, particularly lung cancer. However, systemic GR inhibition or degradation using conventional Proteolysis Targeting Chimeras (PROTACs) risks widespread on-target toxicity due to their constitutive activity. We hypothesized that integrating photoswitchable elements into PROTACs, termed photoPROTACs, would enable wavelength-specific, spatiotemporally precise modulation of GR degradation and dormancy-associated signaling pathways. Here, we synthesized a diverse series of photoPROTACs incorporating photoswitchable arylazotriazole or arylazopyrazole scaffolds, including previously unreported (OEt)2- and (NMe2)2-substituted photoswitches. Arylazopyrazole-based GR photoPROTACs bearing Me2- and (OEt)2 substituents exhibited near-quantitative photoisomerization (95% Z-isomer; 89% – 92% E-isomer), no photobleaching, and thermal half-lives in the range of 3−12.2 days in DMSO. Among them, KH-5-306 and KH-5-309 induced potent, specific, and reversible GR degradation in their thermodynamically stable E-isomeric form at low nanomolar concentrations, with markedly reduced activity in the Z-isomeric state. Transcriptomic profiling showed that E-KH-5-309 disrupts GR-driven dormancy-associated gene expression programs in a non-small lung cancer (NSLC) model, while the Z-isomer remains functionally inert. Our findings establish a framework for the rational design of photoswitchable PROTACs beyond GR and demonstrate their potential to achieve spatiotemporal control of stress hormone receptor signaling, enabling mechanistic insights into GR function and the targeted disruption of cancer cell dormancy.

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