2014
DOI: 10.18632/oncotarget.2337
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Catalytic mTOR inhibitors can overcome intrinsic and acquired resistance to allosteric mTOR inhibitors

Abstract: 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 rapamycinsensitive 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 rapamyc… Show more

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Cited by 58 publications
(48 citation statements)
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References 65 publications
(75 reference statements)
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“…These pilot data suggest that oncogenic changes in KRAS and BRAF are associated with resistance to mTOR inhibitors, a finding that has been observed in other disease sites [52,72].…”
Section: Biomarkers Associated With Response To Pi3k Pathway Inhibitionsupporting
confidence: 58%
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“…These pilot data suggest that oncogenic changes in KRAS and BRAF are associated with resistance to mTOR inhibitors, a finding that has been observed in other disease sites [52,72].…”
Section: Biomarkers Associated With Response To Pi3k Pathway Inhibitionsupporting
confidence: 58%
“…While clearly necessary, this high risk infection is not sufficient as only a small minority, roughly 4% of women with HPV infections develop dysplasia or malignancy [52,53].…”
Section: Cervical Cancermentioning
confidence: 99%
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“…There is also in vitro evidence that acquired mTOR mutations could result in resistance to rapamycin, as documented by a recent study where breast cancer BT474 cells were rendered resistant to rapamycin by prolonged culturing with increasing concentrations of the drug [69]. Rapamycin-resistant BT474 cells displayed a S2035F mutation in the FRB domain of mTOR.…”
Section: Reviewmentioning
confidence: 95%
“…Studies on the PI3K/PTEN/AKT/mTOR1/S6K1 pathway reveal clear discrepancies among drug efficacy readouts at the target, pathway and cellular levels for different cancer cell lines (Hassan et al, 2014;Santiskulvong et al, 2011;Shoji et al, 2012). These observed discrepancies are likely due to a mix of the complexity of the signalling network and its mutations together with fundamental differences in enzyme kinetics in various cellular environments.…”
Section: Accepted Manuscriptmentioning
confidence: 99%