Overcoming mTOR resistance mutations with a new-generation mTOR inhibitor.
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.
Program in Molecular Pharmacology, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
Vanessa S
VS
Rodrik-Outmezguine
Howard Hughes Medical Institute and Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, California 94158, USA.
Masanori
M
Okaniwa
Program in Molecular Pharmacology, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
Zhan
Z
Yao
Howard Hughes Medical Institute and Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, California 94158, USA.
Chris J
CJ
Novotny
AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK.
Claire
C
McWhirter
Program in Molecular Pharmacology, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
Arpitha
A
Banaji
Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
Helen
H
Won
Anti-Tumor Assessment Core, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
Wai
W
Wong
Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
Mike
M
Berger
Anti-Tumor Assessment Core, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
Elisa
E
de Stanchina
AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK.
Derek G
DG
Barratt
AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK.
Sabina
S
Cosulich
AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK.
Teresa
T
Klinowska
Program in Molecular Pharmacology, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.|Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
Neal
N
Rosen
Howard Hughes Medical Institute and Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, California 94158, USA.|Department of Chemistry, University of California Berkeley, Berkeley, California 94720, USA.
Kevan M
KM
Shokat
D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D045744:Cell Line, Tumor; D004351:Drug Resistance / Q000187:drug effects* / Q000235:genetics*; D005260:Female; D006801:Humans; D051379:Mice; D009154:Mutation / Q000187:drug effects / Q000235:genetics*; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000145:classification / Q000494:pharmacology*; D017434:Protein Structure, Tertiary / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D047428:Protein Kinase Inhibitors; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases