Discovery of drug-resistant and drug-sensitizing mutations in the oncogenic PI3K isoform p110 alpha

Cancer Cell. 2008 Aug 12;14(2):180-92. doi: 10.1016/j.ccr.2008.06.014.


p110 alpha (PIK3CA) is the most frequently mutated kinase in human cancer, and numerous drugs targeting this kinase are currently in preclinical development or early-stage clinical trials. Clinical resistance to protein kinase inhibitors frequently results from point mutations that block drug binding; similar mutations in p110 alpha are likely, but currently none have been reported. Using a S. cerevisiae screen against a structurally diverse panel of PI3K inhibitors, we have identified a potential hotspot for resistance mutations (I800), a drug-sensitizing mutation (L814C), and a surprising lack of resistance mutations at the "gatekeeper" residue. Our analysis further reveals that clinical resistance to these drugs may be attenuated by using multitargeted inhibitors that simultaneously inhibit additional PI3K pathway members.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic / drug effects
  • Class I Phosphatidylinositol 3-Kinases
  • Drug Resistance, Neoplasm* / drug effects
  • Epidermal Growth Factor / pharmacology
  • Humans
  • Isoenzymes / metabolism
  • Mice
  • Mutagenesis / drug effects
  • Mutant Proteins / metabolism
  • Mutation / genetics*
  • Oncogene Proteins / metabolism*
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphorylation / drug effects
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins c-akt / metabolism
  • Saccharomyces cerevisiae / growth & development


  • Isoenzymes
  • Mutant Proteins
  • Oncogene Proteins
  • Protein Kinase Inhibitors
  • Epidermal Growth Factor
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CA protein, human
  • Proto-Oncogene Proteins c-akt