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 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.

Emerging strategies for targeting PI3K in gynecologic cancer

“…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].…”

“…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].…”

“…Clinically, this resulted in potent progression of disease in breast carcinoma with single everolimus and a next generation of mTORC1/mTORC2 inhibitors has been developed to abrogate this feedback loop [52].…”

Current treatment strategies for inhibiting mTOR in cancer

“…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.…”

Kinetic modelling of in vitro data of PI3K, mTOR1, PTEN enzymes and on-target inhibitors Rapamycin, BEZ235, and LY294002

“…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.…”