Targeting AKT and CK2 represents a novel therapeutic strategy for SMO constitutive activation-driven medulloblastoma

Aims: Sonic hedgehog subtype medulloblastoma is featured with overactivation of hedgehog pathway and can be targeted by SMO-specific inhibitors. However, the resistance is frequently developed leading to treatment failure of SMO inhibitors. W535L mutation of SMO (SMO^W535L ) is thought to be an oncogenic driver for Sonic hedgehog subtype MB and confer resistance to SMO inhibitors. The regulation network of SMO^W535L remains to be explored in comparison with wild-type SMO (SMO^WT ).

Methods: In this study, we profiled transcriptomes, methylomes, and interactomes of MB cells expression SMOWT or SMOW535L in the treatment of DMSO or SMO inhibitor, respectively.

Results: Analysis of transcriptomic data indicated that SMO inhibitor disrupted processes of endocytosis and cilium organization in MB cells with SMO^WT , which are necessary for SMO activation. In MB cells with SMO^W535L , however, SMO inhibitor did not affect the two processes-related genes, implying resistance of SMO^W535L toward SMO inhibitor. Moreover, we noticed that SMO inhibitor significantly inhibited metabolism-related pathways. Our metabolic analysis indicated that nicotinate and nicotinamide metabolism, glycerolipid metabolism, beta-alanine metabolism, and synthesis and degradation of ketone bodies might be involved in SMO^W535L function maintenance. Interactomic analysis revealed casein kinase II (CK2) as an important SMO-associated protein. Finally, we linked CK2 and AKT together and found combination of inhibitors targeting CK2 and AKT showed synergetic effects to inhibit the growth of MB cells with SMO constitutive activation mutation.

Conclusions: Taken together, our work described SMO-related transcriptomes, metabolomes, and interactomes under different SMO status and treatment conditions, identifying CK2 and AKT as therapeutic targets for SHH-subtype MB cells with SMO inhibitor resistance.