UCSF

Drug resistance is a seemingly inescapable fact in cancer therapy. This is particularly true for anti-cancer protein kinase inhibitors, which can be remarkably successful, but inevitably fall victim to resistance - leading to patient relapse. The most frequent mechanism of resistance is mutations in the target protein kinase that preclude inhibitor binding, and the discovery and characterization of these mutations has led to second generation kinase inhibitors that can overcome the initial drug-resistant mutations. The related PI3K inhibitors show much promise as anti-cancer therapy, but are likely to be just as susceptible to drug resistance by mutation of the target kinase. The oncogenic PI3K isoform p110α is the most frequently mutated kinase in human cancer, and numerous drugs targeting this kinase are currently in pre-clinical development or early stage clinical trials. Clinical resistance mutations appear likely, but currently none have been reported. Using a S. cerevisiae screen against a structurally diverse panel of PI3K inhibitors, I have identified a potential hotspot for resistance mutations (Ile 800), a drug-sensitizing mutation (Lys814Cys), and a surprising lack of resistance mutations at the gatekeeper residue (Ile 848). The screening protocol described here is applicable to several other drug targets that inhibit S. cerevisiae growth in addition to p110α, and hopefully will be used as part of a broader trend in drug development to predict drug-resistant mutations in the laboratory rather than waiting for them to occur in patients, in order to accelerate the development of second-generation inhibitors.