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Overcoming mTOR resistance mutations with a new-generation mTOR inhibitor
Open accessAbstract
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, 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. 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.
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Metadata
- Authors
- Rodrik-Outmezguine, V. S., Okaniwa, M., Yao, Z., Novotny, C. J., McWhirter, C., Banaji, A., Won, H., Wong, W., Berger, M., de Stanchina, E., Barratt, D. G., Cosulich, S., Klinowska, T., Rosen, N., & Shokat, K. M.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Howard Hughes Medical Institute (US)
- AstraZeneca (United Kingdom) (GB)
- Corresponding author
- Rosen, Neal
- Shokat, Kevan M.
- ORCID
- Venue
- Nature
- Published
- 2016-05-18
- Volume
- 534
- Issue
- 7606
- Pages
- 272-276
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4902179
- OpenAlex
- W2407198816
- Cited by
- 479
- References
- 28
- Citations by year
- 2026: 28 · 2025: 48 · 2024: 41 · 2023: 56 · 2022: 51 · 2021: 63 · 2020: 49 · 2019: 34 · 2018: 47 · 2017: 44 · 2016: 16
- FWCI
- 24.42
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institute on Alcohol Abuse and Alcoholism (P50AA017072)
- National Cancer Institute (P01CA129243, P01CA094060, P30CA008748)
- National Institute of General Medical Sciences (T32GM064337)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Health Sciences › Medicine › Oncology › Advanced Breast Cancer Therapies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- mTOR kinase, drug resistance, mTOR inhibitors, kinase domain mutations, rapalogs, cancer therapy resistance, tumor growth inhibition
- MeSH terms
- Animals, Binding Sites, Drug Resistance, Female, Humans, Mutation, Neoplasms, Signal Transduction, Protein Structure, Tertiary, Xenograft Model Antitumor Assays, Cell Line, Tumor, Protein Kinase Inhibitors, Mice, TOR Serine-Threonine Kinases
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