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

Burhan Hassan, Argun Akcakanat, Takafumi Sangai, Kurt W. Evans, Farrell Adkins, Agda Karina Eterovic, Hao Zhao, Ken Chen, Huiqin Chen, Kim Anh Do, Shelly M. Xie, Ashley M. Holder, Aung Naing, Gordon B. Mills, Funda Meric-Bernstam

    Research output: Contribution to journalArticle

    38 Scopus citations

    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.

    Original languageEnglish (US)
    Pages (from-to)8544-8557
    Number of pages14
    JournalOncotarget
    Volume5
    Issue number18
    DOIs
    StatePublished - Jan 1 2014

    Keywords

    • Akt
    • Breast cancer
    • Everolimus
    • Rapamycin
    • mTOR

    ASJC Scopus subject areas

    • Oncology

    Fingerprint Dive into the research topics of 'Catalytic mTOR inhibitors can overcome intrinsic and acquired resistance to allosteric mTOR inhibitors'. Together they form a unique fingerprint.

  • Cite this

    Hassan, B., Akcakanat, A., Sangai, T., Evans, K. W., Adkins, F., Eterovic, A. K., Zhao, H., Chen, K., Chen, H., Do, K. A., Xie, S. M., Holder, A. M., Naing, A., Mills, G. B., & Meric-Bernstam, F. (2014). Catalytic mTOR inhibitors can overcome intrinsic and acquired resistance to allosteric mTOR inhibitors. Oncotarget, 5(18), 8544-8557. https://doi.org/10.18632/oncotarget.2337