DYRK2 inhibition overcomes resistance to SMO inhibitors in Hedgehog-driven tumors

Hedgehog (Hh) signaling is frequently activated in cancers, such as basal cell carcinoma and medulloblastoma. Although Smoothened (SMO) inhibitors such as vismodegib and sonidegib are used to treat Hh-driven tumors, their efficacy is often limited by drug-resistant SMO mutations. Here, we investigated whether targeting DYRK2, a positive regulator of Hh signaling downstream of SMO, suppresses Hh signaling driven by the drug-resistant SMO^W535L mutation. Genetic depletion and pharmacological inhibition of DYRK2 suppressed Hh target gene expression in SMO^W535L-expressing cells. In contrast to vismodegib, DYRK2 inhibition reduced oncosphere formation in SMO^W535L-expressing medulloblastoma cells. These findings identify DYRK2 as a regulatory node downstream of SMO and demonstrate that targeting DYRK2 represents a strategy to overcome resistance to SMO inhibitors in Hh-driven tumors.