PIK3CA/PTEN mutations and Akt activation as markers of sensitivity to allosteric mTOR inhibitors

Funda Meric-Bernstam, Argun Akcakanat, Huiqin Chen, Kim Anh Do, Takafumi Sangai, Farrell Adkins, Ana Maria Gonzalez-Angulo, Asif Rashid, Katherine Crosby, Mei Dong, Alexandria T. Phan, Robert A. Wolff, Sanjay Gupta, Gordon B. Mills, James Yao

    Research output: Contribution to journalArticle

    155 Scopus citations

    Abstract

    Purpose: We sought to determine whether phosphoinositide 3-kinase (PI3K) pathway mutation or activation state and rapamycin-induced feedback loop activation of Akt is associated with rapamycin sensitivity or resistance. Experimental Design: Cancer cell lines were tested for rapamycin sensitivity, Akt phosphorylation, and mTOR target inhibition. Mice injected with breast or neuroendocrine cancer cells and patients with neuroendocrine tumor (NET) were treated with rapalogs and Akt phosphorylation was assessed. Results: Thirty-one cell lines were rapamycin sensitive (RS) and 12 were relatively rapamycin resistant (RR; IC 50> 100 nmol/L). Cells with PIK3CA and/or PTEN mutations were more likely to be RS (P=0.0123). Akt phosphorylation (S473 and T308) was significantly higher in RS cells (P < 0.0001). Rapamycin led to a significantly greater pathway inhibition and greater increase in p-Akt T308 (P < 0.0001) and p-Akt S473 (P=0.0009) in RS cells. Rapamycin and everolimus significantly increased Akt phosphorylation but inhibited growth in an in vivo NET model (BON). In patients with NETs treated with everolimus and octreotide, progression-free survival correlated with p-Akt T308 in pretreatment (R = 0.4762, P = 0.0533) and ontreatment tumor biopsies (R = 0.6041, P = 0.0102). Patients who had a documented partial response were more likely to have an increase in p-Akt T308 with treatment compared with nonresponders (P = 0.0146). Conclusion: PIK3CA/PTEN genomic aberrations and high p-Akt levels are associated with rapamycin sensitivity in vitro. Rapamycin-mediated Akt activation is greater in RS cells, with a similar observation in patients with clinical responses on exploratory biomarker analysis; thus feedback loop activation of Akt is not a marker of resistance but rather may function as an indicator of rapamycin activity.

    Original languageEnglish (US)
    Pages (from-to)1777-1789
    Number of pages13
    JournalClinical Cancer Research
    Volume18
    Issue number6
    DOIs
    StatePublished - Mar 15 2012

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

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  • Cite this

    Meric-Bernstam, F., Akcakanat, A., Chen, H., Do, K. A., Sangai, T., Adkins, F., Gonzalez-Angulo, A. M., Rashid, A., Crosby, K., Dong, M., Phan, A. T., Wolff, R. A., Gupta, S., Mills, G. B., & Yao, J. (2012). PIK3CA/PTEN mutations and Akt activation as markers of sensitivity to allosteric mTOR inhibitors. Clinical Cancer Research, 18(6), 1777-1789. https://doi.org/10.1158/1078-0432.CCR-11-2123