Catalytic mTOR inhibitors can overcome intrinsic and acquired resistance to allosteric mTOR inhibitors

// Burhan Hassan 1 , Argun Akcakanat 2 , Takafumi Sangai 1 , Kurt W. Evans 2 , Farrell Adkins 1 , Agda Karina Eterovic 3 , Hao Zhao 4 , Ken Chen 4 , Huiqin Chen 5 , Kim-Anh Do 5 , Shelly M. Xie 1 , Ashley M. Holder 1 , Aung Naing 2 , Gordon B. Mills 3 and Funda Meric-Bernstam 1,2 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 Correspondence: Funda Meric-Bernstam, email: // Keywords : mTOR, Akt, rapamycin, everolimus, breast cancer Received : June 10, 2014 Accepted : August 09, 2014 Published : August 10, 2014 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 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.