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

Abstract

Glioblastoma stem-like cells (GSCs) are highly plastic tumor cells that drive initiation, progression and therapeutic resistance. Although lysosomal homeostasis has emerged as a critical determinant of GSC fitness, the molecular mechanisms regulating this compartment remain incompletely understood. Here, using complementary proteomic approaches, we identified a lysosomal signature associated with the kinase CK1 in THP1 monocytic cells. Biochemical analyses revealed that genetic or siRNA-mediated depletion of CK1 altered the overall abundance and maturation of late endosome-lysosome-associated proteins in both THP1 cells and two patient-derived GSCs. This lysosomal remodeling was associated with impaired tumorsphere formation capacity in GSCs. To further explore the therapeutic potential of targeting CK1, we employed selective molecular glue degraders (MGDs). Acute CK1 degradation efficiently recapitulated lysosomal remodeling and impaired tumorsphere formation in GSCs. While CK1-targeted MGDs did not sensitize GSCs to lysosomal membrane permeabilization induced by L-leucyl-L-leucine methyl ester (LLOMe), they protected from GPX4 inhibitor-induced ferroptosis. Together, these findings identify CK1 as a regulator of lysosomal fitness and ferroptotic sensitivity, suggesting a connection between CK1-dependent lysosome remodeling and associated cell death pathways.