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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    ABSTRACT: Protein kinases are therapeutic targets for human cancer. However, "gatekeeper" mutations in tyrosine kinases cause acquired clinical resistance, limiting long-term treatment benefits. mTOR is a key cancer driver and drug target. Numerous small-molecule mTOR kinase inhibitors have been developed, with some already in human clinical trials. Given our clinical experience with targeted therapeutics, acquired drug resistance in mTOR is thought likely, but not yet documented. Herein, we describe identification of a hot spot (L2185) for drug-resistant mutations, which is distinct from the gatekeeper site, and a chemical scaffold refractory to drug-resistant mutations. We also provide new insights into mTOR kinase structure and function. The hot spot mutations are potentially useful as surrogate biomarkers for acquired drug resistance in ongoing clinical trials and future treatments and for the design of the next generation of mTOR-targeted drugs. Our study provides a foundation for further research into mTOR kinase function and targeting. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 04/2015; 11(3). DOI:10.1016/j.celrep.2015.03.040 · 8.36 Impact Factor
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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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    ABSTRACT: One of the most important metabolic hallmarks of cancer cells is enhanced lipogenesis. Depending on the tumor type, tumor cells synthesize up to 95% of saturated and mono-unsaturated fatty acids (FA) de novo in spite of sufficient dietary lipid supply. This lipogenic conversion starts early when cells become cancerous and further expands as the tumor cells become more malignant. It is suggested that activation of FA synthesis is required for carcinogenesis and for tumor cell survival. These observations suggest that the enzymes involved in FA synthesis would be rational therapeutic targets for cancer treatment. However, several recent reports have shown that the anti-tumor effects, following inhibition of endogenous FA synthesis in cancer cell lines may be obviated by adding exogenous FAs. Additionally, high intake of dietary fat is reported to be a potential risk factor for development and poor prognosis for certain cancers. Recently it was reported that breast and liposarcoma tumors are equipped for both de novo fatty acid synthesis pathway as well as LPL-mediated extracellular lipolysis. These observations indicate that lipolytically acquired FAs may provide an additional source of FAs for cancer. This review focuses on our current understanding of lipogenic and lipolytic pathways in cancer cell progression.
    Progress in lipid research 08/2013; 52(4). DOI:10.1016/j.plipres.2013.08.005 · 10.02 Impact Factor
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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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    ABSTRACT: Constitutive phosphoinositide 3-kinase (PI3K)/Akt activation is common in T cell acute lymphoblastic leukemia (T-ALL). Although four distinct class I PI3K isoforms (α, β, γ, δ) could participate in T-ALL pathogenesis, none has been implicated in this process. We report that in the absence of PTEN phosphatase tumor suppressor function, PI3Kγ or PI3Kδ alone can support leukemogenesis, whereas inactivation of both isoforms suppressed tumor formation. The reliance of PTEN null T-ALL on the combined activities of PI3Kγ/δ was further demonstrated by the ability of a dual inhibitor to reduce disease burden and prolong survival in mice as well as prevent proliferation and promote activation of proapoptotic pathways in human tumors. These results support combined inhibition of PI3Kγ/δ as therapy for T-ALL.
    Cancer cell 04/2012; 21(4):459-72. DOI:10.1016/j.ccr.2012.02.029 · 23.52 Impact Factor
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