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 Mills, James Yao

Research output: Contribution to journalArticle

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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
Externally publishedYes

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Sirolimus
Mutation
Phosphorylation
Neuroendocrine Tumors
Cell Line
Neoplasms
Neuroendocrine Cells
1-Phosphatidylinositol 4-Kinase
Octreotide
Disease-Free Survival
Breast
Research Design
Biomarkers

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Meric-Bernstam, F., Akcakanat, A., Chen, H., Do, K. A., Sangai, T., Adkins, F., ... 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

PIK3CA/PTEN mutations and Akt activation as markers of sensitivity to allosteric mTOR inhibitors. / Meric-Bernstam, Funda; Akcakanat, Argun; Chen, Huiqin; Do, Kim Anh; Sangai, Takafumi; Adkins, Farrell; Gonzalez-Angulo, Ana Maria; Rashid, Asif; Crosby, Katherine; Dong, Mei; Phan, Alexandria T.; Wolff, Robert A.; Gupta, Sanjay; Mills, Gordon; Yao, James.

In: Clinical Cancer Research, Vol. 18, No. 6, 15.03.2012, p. 1777-1789.

Research output: Contribution to journalArticle

Meric-Bernstam, F, Akcakanat, A, Chen, H, Do, KA, Sangai, T, Adkins, F, Gonzalez-Angulo, AM, Rashid, A, Crosby, K, Dong, M, Phan, AT, Wolff, RA, Gupta, S, Mills, G & Yao, J 2012, 'PIK3CA/PTEN mutations and Akt activation as markers of sensitivity to allosteric mTOR inhibitors', Clinical Cancer Research, vol. 18, no. 6, pp. 1777-1789. https://doi.org/10.1158/1078-0432.CCR-11-2123
Meric-Bernstam, Funda ; Akcakanat, Argun ; Chen, Huiqin ; Do, Kim Anh ; Sangai, Takafumi ; Adkins, Farrell ; Gonzalez-Angulo, Ana Maria ; Rashid, Asif ; Crosby, Katherine ; Dong, Mei ; Phan, Alexandria T. ; Wolff, Robert A. ; Gupta, Sanjay ; Mills, Gordon ; Yao, James. / PIK3CA/PTEN mutations and Akt activation as markers of sensitivity to allosteric mTOR inhibitors. In: Clinical Cancer Research. 2012 ; Vol. 18, No. 6. pp. 1777-1789.
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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.",
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T1 - PIK3CA/PTEN mutations and Akt activation as markers of sensitivity to allosteric mTOR inhibitors

AU - Meric-Bernstam, Funda

AU - Akcakanat, Argun

AU - Chen, Huiqin

AU - Do, Kim Anh

AU - Sangai, Takafumi

AU - Adkins, Farrell

AU - Gonzalez-Angulo, Ana Maria

AU - Rashid, Asif

AU - Crosby, Katherine

AU - Dong, Mei

AU - Phan, Alexandria T.

AU - Wolff, Robert A.

AU - Gupta, Sanjay

AU - Mills, Gordon

AU - Yao, James

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N2 - 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.

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