Catalytic mTOR inhibitors can overcome intrinsic and acquired resistance to allosteric mTOR inhibitors
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Burhan Hassan1, Argun Akcakanat2, Takafumi Sangai1, Kurt W. Evans2, Farrell Adkins1, Agda Karina Eterovic3, Hao Zhao4, Ken Chen4, Huiqin Chen5, Kim-Anh Do5, Shelly M. Xie1, Ashley M. Holder1, Aung Naing2, Gordon B. Mills3 and Funda Meric-Bernstam1,2
1 Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
2 Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX
3 Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX
4 Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX
5 Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX
Funda Meric-Bernstam, email:
Keywords: mTOR, Akt, rapamycin, everolimus, breast cancer
Received: June 10, 2014 Accepted: August 09, 2014 Published: August 10, 2014
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.
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