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Overcoming mTOR resistance mutations with a new-generation mTOR inhibitor

机译：用新一代mTOR抑制剂克服mTOR抗性突变

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摘要

Precision medicines exert selective pressure on tumour cells that leads to the preferential growth of resistant subpopulations, necessitating the development of next-generation therapies to treat the evolving cancer. The PIK3CA-AKT-mTOR pathway is one of the most commonly activated pathways in human cancers(1), which has led to the development of small-molecule inhibitors that target various nodes in the pathway. Among these agents, first-generation mTOR inhibitors (rapalogs) have caused responses in 'N-of-1' cases, and second-generation mTOR kinase inhibitors (TORKi) are currently in clinical trials(2-4). Here we sought to delineate the likely resistance mechanisms to existing mTOR inhibitors in human cell lines, as a guide for next-generation therapies. The mechanism of resistance to the TORKi was unusual in that intrinsic kinase activity of mTOR was increased, rather than a direct active-site mutation interfering with drug binding. Indeed, identical drug-resistant mutations have been also identified in drug-naive patients, suggesting that tumours with activating MTOR mutations will be intrinsically resistant to second-generation mTOR inhibitors. We report the development of a new class of mTOR inhibitors that overcomes resistance to existing first-and second-generation inhibitors. The third-generation mTOR inhibitor exploits the unique juxtaposition of two drug-binding pockets to create a bivalent interaction that allows inhibition of these resistant mutants.
机译：精密药物对肿瘤细胞施加选择性压力，导致抗性亚群的优先生长，因此有必要开发下一代疗法来治疗不断发展的癌症。 PIK3CA-AKT-mTOR途径是人类癌症中最常激活的途径之一（1），这导致了靶向该途径中各个节点的小分子抑制剂的发展。在这些药物中，第一代mTOR抑制剂（rapalogs）在'N-of-1'病例中引起了反应，第二代mTOR激酶抑制剂（TORKi）目前正在临床试验中（2-4）。在这里，我们试图描述对人类细胞系中现有mTOR抑制剂的可能耐药机制，以作为下一代疗法的指南。对TORKi的抗性机制与众不同，因为它增加了mTOR的内在激酶活性，而不是直接的活性位点突变干扰了药物结合。确实，在未经药物治疗的患者中也鉴定出相同的耐药突变，这表明具有活化MTOR突变的肿瘤将固有地对第二代mTOR抑制剂具有耐药性。我们报告了新型mTOR抑制剂的开发，该抑制剂克服了对现有第一代和第二代抑制剂的耐药性。第三代mTOR抑制剂利用两个药物结合口袋的独特并置来创建二价相互作用，从而抑制这些耐药突变体。

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  • 来源
    《Nature》 |2016年第7606期|272-276|共5页
  • 作者

    Rodrik-Outmezguine Vanessa S.; Okaniwa Masanori; Yao Zhan; Novotny Chris J.; McWhirter Claire; Banaji Arpitha; Won Helen; Wong Wai; Berger Mike; de Stanchina Elisa; Barratt Derek G.; Cosulich Sabina; Klinowska Teresa; Rosen Neal; Shokat Kevan M.;

  • 作者单位

    Mem Sloan Kettering Canc Ctr, Program Mol Pharmacol, New York, NY 10065 USA;

    Univ Calif San Francisco, Howard Hughes Med Inst, San Francisco, CA 94158 USA|Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94158 USA;

    Mem Sloan Kettering Canc Ctr, Program Mol Pharmacol, New York, NY 10065 USA;

    Univ Calif San Francisco, Howard Hughes Med Inst, San Francisco, CA 94158 USA|Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94158 USA;

    AstraZeneca, Alderley Pk, Macclesfield SK10 4TG, Cheshire, England;

    Mem Sloan Kettering Canc Ctr, Program Mol Pharmacol, New York, NY 10065 USA;

    Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA;

    Mem Sloan Kettering Canc Ctr, Antitumor Assessment Core, New York, NY 10065 USA;

    Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA;

    Mem Sloan Kettering Canc Ctr, Antitumor Assessment Core, New York, NY 10065 USA;

    AstraZeneca, Alderley Pk, Macclesfield SK10 4TG, Cheshire, England;

    AstraZeneca, Alderley Pk, Macclesfield SK10 4TG, Cheshire, England;

    AstraZeneca, Alderley Pk, Macclesfield SK10 4TG, Cheshire, England;

    Mem Sloan Kettering Canc Ctr, Program Mol Pharmacol, New York, NY 10065 USA|Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA;

    Univ Calif San Francisco, Howard Hughes Med Inst, San Francisco, CA 94158 USA|Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94158 USA|Univ Calif Berkeley, Dept Chem, Berkeley, CA 94720 USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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