Discovery of Drug-Resistant and Drug-Sensitizing Mutations in the Oncogenic PI3K Isoform p110α

Graduate Group in Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA.
Cancer cell (Impact Factor: 23.52). 09/2008; 14(2):180-92. DOI: 10.1016/j.ccr.2008.06.014
Source: PubMed


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.

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    • "Strikingly, only the I2237L mutation fully preserves mTOR kinase function (Figures 3D and 3E), suggesting that mTOR's gatekeeper position does not tolerate any substitution except the highly conserved leucine, which explains the lack of drug-resistant gatekeeper mutations. A similar phenomenon was also observed with another atypical kinase, PI3Ka (Zunder et al., 2008), suggesting that mTOR and PI3K are similar with respect to the function of the gatekeeper residue. "
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    • "Fatty acids can also be used for the biosynthesis of an array of protumorigenic lipid-signaling molecules. A lipid messenger considered to be particularly important in contributing to cancer is phosphatidylinositol-3,4,5-trisphosphate [PI(3,4,5)P3], a molecule that is formed by the action of phosphatidylinositol-3-kinase and activates protein kinase B/Akt to stimulate cell proliferation and survival [16] [17]. Other prominent examples of lipid messengers are lysophosphatidic acid (LPA) that signals through a family of G protein-coupled receptors to promote cancer aggressiveness [18], and prostaglandins, a class of lipid messengers that are formed by cyclooxygenases and support migration and tumor-host interactions [19] [20]. "
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    • "Previously, it has been reported that p110a is involved in oncogenesis because function-enhancing mutations in this catalytic subunit are found in many cancers of solid organs (Samuels et al., 2004; Zunder et al., 2008). In contrast, cancer-specific mutations have yet to be identified for the other p110 isoforms. "
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