Smoother tumor targets

Texas researchers have identified two kinases-GRK2 and CKI-a-that are responsible for phosphorylating smoothened, the central player in the hedgehog signaling pathway.¹ The findings could open a new front against the tumor-promoting pathway if sufficiently selective inhibitors can be developed.

Because G protein-coupled receptor kinase 2 (GRK2; GPRK2) and casein kinase 1a (CSNK1A; CKI-a) help bring smoothened (SMO) to a cellular structure in which SMOreceives a proliferative signal, blocking them mightovercome activating mutations in SMO that cause resistance to SMO antagonists.

Three antagonists of SMOare in Phase II testing for various solid tumors: vismodegib (GDC-0449), jointly developed byRoche'sGenentech Inc.unit andCuris Inc.,IPI-926 from Infinity Pharmaceuticals Inc.and Mundipharma International Ltd. and LDE225 from Novartis AG.

Last week, Roche presented additional data from a Phase II trial of vismodegib in basal cell carcinoma (BCC). The trial met its endpoints of increased overall response rate