Treatment Duration Increment and Pharmacodynamic Study of CX-4945 in Patients With Basal Cell Carcinoma (BCC)

Basal cell carcinomas require the hedgehog (Hh) pathway for growth. Hh binding relieves the inhibitory effect of PTCH1 on Smoothened (SMO). Signal transduction by SMO then leads to the activation and nuclear localization of GLI1 transcription factors and induction of Hh target genes, many of which are involved in proliferation, survival, and angiogenesis. Hedgehog pathway inhibitors, such as vismodegib6 and sonidegib phosphate, target the G-protein-coupled receptor Smoothened (SMO) and are recommended as first-line treatment for advanced BCC or mBCC by the National Comprehensive Cancer Network. CK2 affects the terminal-most Hh signaling components. Given the roles of CK2 on the terminal step of the hedgehog signaling pathway, CK2 inhibition is unlikely to be overcome by downstream mutations within this pathway. These data thus suggest an immediately practical application of CX-4945 in Hh-driven tumors and possibly tumors resistant to SMO inhibitors.