Molecular glue degraders of CK1α remodel lysosomes and limit ferroptosis in glioblastoma stem-like cells

Acute CK1 degradation in glioblastoma stem-like cells remodels lysosomes and limits GPX4 inhibitor-induced ferroptosis, while not sensitizing to LLOMe-induced lysosomal membrane permeabilization.

• Why it matters: Lysosomal homeostasis is linked to glioblastoma stem-like cell fitness, but how CK1 regulates lysosome remodeling and downstream death pathways is unclear.
• What they did: Proteomic profiling in THP1 monocytic cells identified a lysosomal CK1-associated signature; CK1 depletion (genetic or siRNA) altered late endosome-lysosome protein abundance and maturation in THP1 and two patient-derived GSCs, and selective CK1 molecular glue degraders were tested in GSCs.
• The result: CK1 degradation recapitulated lysosomal remodeling and impaired tumorsphere formation, and it protected GSCs from GPX4 inhibitor-induced ferroptosis without sensitizing them to LLOMe-induced lysosomal membrane permeabilization.