Curis Inc (CRIS)

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Acquired resistance to tyrosine kinase inhibitors, similar

Frederic de Sauvage and colleagues examine the mechanism of resistance.

The authors examined the mutation status of hedgehog pathway components in a tumour sample obtained following the patient's relapse and discovered a G to C mutation in SMO that changed the aspartic acid at position 473 to histidine (D473H). This mutation was not present in normal skin

... in response to SMO-D473H, indicating that the mutation leads to GDC-0449 resistance without compromising hedgehog pathway activation by SMO. Binding assays with 14C-labelled GDC-0449 showed that the drug could not specifically bind SMO-D473H.

Although initial clinical trial data with GDC-0449 have been positive, it seems that tumours are likely to acquire resistance to inhibitors of G protein-coupled receptors such as SMO, like they do to tyrosine kinase inhibitors, emphasizing the need to identify ways in which resistance can be circumvented.

http://www.medscape.com/viewarticle/715704

GDC-0449 is very effective until some BCC and meduloblastoma patients develop resistance? Not likely the resistance can be reversed.
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Published Online 2 September 2009
Looks like old news. A better link for those interested

http://www.sciencemag.org/content/326/5952/572.figures-only