Therapeutic resistance: Smoothing the way

using hedgehog pathway inhibitors to treat both medulloblastoma and basal cell carcinoma. Phase I clinical trial data in basal cell carcinoma and a case study of a patient with medullo­ blastoma reported recently in the New England Journal of Medicine have shown that GDC­0449, which inhibits hedgehog signalling by binding to the smoothened (SMO) receptor, exhibits anti­tumour activity. Although signifi­ cant tumour regression was observed in the patient with medulloblastoma, the tumour developed resistance to GDC­0449 and the disease pro­ gressed. This prompted Frederic de Sauvage and colleagues to examine the mechanism of resistance. Prior to treatment, the medullo­ blastoma had a somatic mutation in the inhibitory receptor patched 1 (PTCH1) that abrogated SMO repression, indicating the importance of activated hedgehog signalling in driving carcinogenesis in this patient and the therapeutic rationale for using GDC­0449. 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 posi­ tion 473 to histidine (D473H). This mutation was not present in normal skin samples or tumour samples obtained prior to GDC­0449 treat­ ment, nor was it found in 64 other medulloblastoma samples. What are the functional conse­ quences of the D473H mutation in SMO? SMO­D473H could activate hedgehog signalling (as assessed by a GLI­luciferase reporter construct) when expressed in fibroblasts, but GDC­0449 was unable to inhibit GLI­luciferase activity in response to SMO­D473H, indicating that the mutation leads to GDC­0449 resistance without compromising hedgehog pathway activation by SMO. Binding assays with 14C­labelled GDC­0449 showed that the drug could not specifically bind SMO­D473H. To mimic this acquired resistance in mice, the authors used subcutane­ ous allografts of medulloblastoma tumours from Ptch1+/–;Trp53–/– mice. Mice were given suboptimal doses of GDC­0449 until the tumours no longer responded to the drug, and three resistant tumour lines were established. In one, the authors identified a mutation that resulted in an aspartic acid to glycine change at position 477 in mouse SMO, which corresponds to D473 in human SMO. Smo mutations were not identified in the two other resistant lines, indicating that resistance to GDC­0449 can be acquired through alternative mechanisms. Although initial clinical trial data with GDC­0449 have been positive, it seems that tumours are likely to acquire resistance to inhibitors of G protein­coupled receptors such as SMO, like they do to tyrosine kinase inhibitors, emphasizing the need to identify ways in which resistance can be circumvented. Sarah Seton-Rogers