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Smoothening resistance

Novartis AG researchers have uncovered three possible molecular causes for brain tumor resistance to inhibitors of Smoothened, which is a key component of the Hedgehog pathway.1 The pharma has used the discovery to devise combination therapies that may bypass some cases of resistance.

Smoothened (SMO) is a G protein-coupled receptor that sends a proliferative signal in many cancers, including basal cell carcinoma (BCC) and medulloblastoma, a common pediatric brain tumor. SMO is activated by mutations in patched 1 (PTCH1) or excess production of sonic hedgehog homolog (SHH).

The most advanced SMO antagonist is GDC-0449 from Roche's Genentech Inc.unit, Chugai Pharmaceutical Co. Ltd.and Curis Inc. It is in Phase II testing for BCC, colorectal cancer and ovarian cancer and in Phase I trials

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