Cited by 504PI3K/AKT/mTOR signaling in cancerAdvanced Breast Cancer TherapiesProtein Kinase Regulation and GTPase Signaling

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Overcoming mTOR resistance mutations with a new-generation mTOR inhibitor

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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.·2016·Nature

DOI 10.1038/nature17963PMC PMC4902179

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Abstract

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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Additional file 8 of mTOR activation induces endolysosomal remodeling and nonclassical secretion of IL-32 via exosomes in inflammatory reactive astrocytes
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Additional file 7 of mTOR activation induces endolysosomal remodeling and nonclassical secretion of IL-32 via exosomes in inflammatory reactive astrocytes
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Additional file 6 of Raptor mediates the selective inhibitory effect of cardamonin on RRAGC-mutant B cell lymphoma
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Additional file 1 of Raptor mediates the selective inhibitory effect of cardamonin on RRAGC-mutant B cell lymphoma
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Additional file 2 of mTOR activation induces endolysosomal remodeling and nonclassical secretion of IL-32 via exosomes in inflammatory reactive astrocytes
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Additional file 2 of mTOR hypoactivity leads to trophectoderm cell failure by enhancing lysosomal activation and disrupting the cytoskeleton in preimplantation embryo
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Additional file 6 of mTOR activation induces endolysosomal remodeling and nonclassical secretion of IL-32 via exosomes in inflammatory reactive astrocytes
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Additional file 4 of mTOR hypoactivity leads to trophectoderm cell failure by enhancing lysosomal activation and disrupting the cytoskeleton in preimplantation embryo
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Additional file 3 of mTOR hypoactivity leads to trophectoderm cell failure by enhancing lysosomal activation and disrupting the cytoskeleton in preimplantation embryo
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Additional file 3 of mTOR activation induces endolysosomal remodeling and nonclassical secretion of IL-32 via exosomes in inflammatory reactive astrocytes
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Additional file 1 of mTOR hypoactivity leads to trophectoderm cell failure by enhancing lysosomal activation and disrupting the cytoskeleton in preimplantation embryo
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Additional file 4 of mTOR activation induces endolysosomal remodeling and nonclassical secretion of IL-32 via exosomes in inflammatory reactive astrocytes
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Additional file 4 of Raptor mediates the selective inhibitory effect of cardamonin on RRAGC-mutant B cell lymphoma
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Additional file 2 of Raptor mediates the selective inhibitory effect of cardamonin on RRAGC-mutant B cell lymphoma
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Additional file 5 of Raptor mediates the selective inhibitory effect of cardamonin on RRAGC-mutant B cell lymphoma
Liu, Y., Zhu, Y., Chen, H., Zhou, J., Niu, P., & Shi, D. (2023) · Figshare · doi:10.6084/m9.figshare.24196817
Additional file 1 of mTOR activation induces endolysosomal remodeling and nonclassical secretion of IL-32 via exosomes in inflammatory reactive astrocytes
Leng, K., Rooney, B., McCarthy, F., Xia, W., Rose, I. V. L., Bax, S., Chin, M. Y., Fathi, S., Herrington, K. A., Leonetti, M. D., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26758862
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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: Rodrik-Outmezguine, Vanessa S.
Okaniwa, Masanori
Yao, Zhan
Novotny, Chris J.
McWhirter, Claire
Won, Helen
Cosulich, Sabina
Klinowska, Teresa
Rosen, Neal
Shokat, Kevan M.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2016-05-18
Volume: 534
Issue: 7606
Pages: 272-276
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature17963
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
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
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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