Catalytic mTOR inhibitors can overcome intrinsic and acquired resistance to allosteric mTOR inhibitors
Copyright policy )Catalytic mTOR inhibitors can overcome intrinsic and acquired resistance to allosteric mTOR inhibitors
We tested the antitumor efficacy of mTOR catalytic site inhibitor MLN0128 in models with intrinsic or acquired rapamycin-resistance. Cell lines that were intrinsically rapamycin-resistant as well as those that were intrinsically rapamycin-sensitive were sensitive to MLN0128 in vitro. MLN0128 inhibited both mTORC1 and mTORC2 signaling, with more robust inhibition of downstream 4E-BP1 phosphorylation and cap-dependent translation compared to rapamycin in vitro. Rapamycin-sensitive BT474 cell line acquired rapamycin resistance (BT474 RR) with prolonged rapamycin treatment in vitro. This cell line acquired an mTOR mutation (S2035F) in the FKBP12-rapamycin binding domain; mTORC1 signaling was not inhibited by rapalogs but was inhibited by MLN0128. In BT474 RR cells, MLN0128 had significantly higher growth inhibition compared to rapamycin in vitro and in vivo. Our results demonstrate that MLN0128 may be effective in tumors with intrinsic as well as acquired rapalog resistance. mTOR mutations are a mechanism of acquired resistance in vitro; the clinical relevance of this observation needs to be further evaluated.
- The University of Texas MD Anderson Cancer Center United States
Benzoxazoles, Mice, Nude, Antineoplastic Agents, Mechanistic Target of Rapamycin Complex 2, Mechanistic Target of Rapamycin Complex 1, Pyrimidines, Allosteric Regulation, Drug Resistance, Neoplasm, Catalytic Domain, Cell Line, Tumor, Drug Design, Multiprotein Complexes, Neoplasms, Mutation, Animals, Humans, Female, Molecular Targeted Therapy, Protein Kinase Inhibitors, Cell Proliferation
Benzoxazoles, Mice, Nude, Antineoplastic Agents, Mechanistic Target of Rapamycin Complex 2, Mechanistic Target of Rapamycin Complex 1, Pyrimidines, Allosteric Regulation, Drug Resistance, Neoplasm, Catalytic Domain, Cell Line, Tumor, Drug Design, Multiprotein Complexes, Neoplasms, Mutation, Animals, Humans, Female, Molecular Targeted Therapy, Protein Kinase Inhibitors, Cell Proliferation
selected citations These citations are derived from selected sources.This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).59 popularity This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.Top 10% influence This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).Top 10% impulse This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.Top 10%
Citations provided by BIP!Popularity provided by BIP!