Q&A: William Sellers on success in small molecules. Interview by Eric Bender.

one could never make any progress. What’s intriguing is that if you look at the situations that we know the best so far, in the targeted therapeutic area, in most cases the mechanism of resistance reactivates the original pathway that was activated by mutations in the first place. In the case of BCR-ABL, the mutations that block the binding of Gleevec to ABL are the most prevalent form of therapeutic resistance. I think this is quite amazing. The second-generation effective therapeutics in that disease are all attacking BCR-ABL again. Unlike chemotherapy resistance, in the targeted area you can define genetic model systems in which the mechanisms of resistance are often the same that you see in humans. That gives us great hope that we can study these mechanisms very early in the clinical development process. For example, before our Smoothened inhibitor (for Ptch mutations in pediatric medulloblastoma and adult basal cell carcinoma) even went into the clinic, we had defined mechanisms of resistance and started to understand drug combinations that might prevent resistance.