title: Identification of a Non-Gatekeeper Hot Spot for Drug-Resistant Mutations in mTOR Kinase.
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.
authors: Rutgers Cancer Institute of New Jersey and Division of Cancer Pharmacology, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ 08903, USA; The Graduate Program in Cellular and Molecular Pharmacology, Rutgers University, Piscataway, NJ 08854, USA.
authors: Tzung-Ju
authors: TJ
authors: Wu
authors: Rutgers Cancer Institute of New Jersey and Division of Cancer Pharmacology, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ 08903, USA; The Graduate Program in Cellular and Molecular Pharmacology, Rutgers University, Piscataway, NJ 08854, USA.
authors: Xiaowen
authors: X
authors: Wang
authors: Rutgers Cancer Institute of New Jersey and Division of Cancer Pharmacology, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ 08903, USA.
authors: Yanjie
authors: Y
authors: Zhang
authors: Rutgers Cancer Institute of New Jersey and Division of Cancer Pharmacology, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ 08903, USA.
authors: Linghua
authors: L
authors: Meng
authors: Rutgers Cancer Institute of New Jersey and Division of Cancer Pharmacology, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ 08903, USA.
authors: John E
authors: JE
authors: Kerrigan
authors: Rutgers Center for Integrated Proteomic Research, Rutgers University, Piscataway, NJ 08854, USA.
authors: Stephen K
authors: SK
authors: Burley
authors: Rutgers Cancer Institute of New Jersey and Division of Cancer Pharmacology, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ 08903, USA. Electronic address: zhengst@cinj.rutgers.edu.
authors: X F Steven
authors: XF
authors: Zheng
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005260:Female; D064593:Heterografts; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D012441:Saccharomyces cerevisiae; D058570:TOR Serine-Threonine Kinases / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism
chemical_list: D058570:TOR Serine-Threonine Kinases