Compensatory activation of Akt in response to mTOR and Raf inhibitors – A rationale for dual-targeted therapy approaches in neuroendocrine tumor disease

Zitzmann, Kathrin; Rüden, Janina von; Brand, Stephan; Göke, Burkhard; Lichtl, J; Spöttl, Gerald; Auernhammer, Christoph J.

doi:10.1016/j.canlet.2010.02.018

Cited by 118 publications

(125 citation statements)

References 32 publications

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“…Consistent with the previous studies on other tumor entities, perifosine significantly reduced the phosphorylation levels of the known Akt downstream targets GSK3a/b, MDM2, and p70S6K. In addition, perifosine also inhibited RAF-MEK-ERK1/2 signaling, a critical pathway for NET cell viability (Zitzmann et al 2010). Recently, it has been shown that like Akt, ERK1/2 may also be upregulated in response to mTOR inhibition, thus potentially limiting the antitumor efficacy of mTOR inhibitors (Carracedo et al 2008, Zitzmann et al 2010, Svejda et al 2011.…”

Section: Discussionsupporting

confidence: 87%

“…In addition, perifosine also inhibited RAF-MEK-ERK1/2 signaling, a critical pathway for NET cell viability (Zitzmann et al 2010). Recently, it has been shown that like Akt, ERK1/2 may also be upregulated in response to mTOR inhibition, thus potentially limiting the antitumor efficacy of mTOR inhibitors (Carracedo et al 2008, Zitzmann et al 2010, Svejda et al 2011. direct Akt inhibition with perifosine appears to have a more broad inhibitory effect on the PI(3)K-AktmTOR pathway without compensatory activation of PI(3)K and ERK1/2 signaling.…”

Section: Discussionmentioning

confidence: 97%

“…Perifosine causes growth inhibition in various tumor cell lines and was also shown to sensitize tumor cells to conventional therapeutic antitumor agents and radiation (Momota et al 2005, Rahmani et al 2005, Vink et al 2006. As mTOR inhibition may result in the activation of upstream PI(3)K/Akt neuroendocrine signaling (Zitzmann et al 2010), direct Akt inhibition with perifosine could suppress this compensatory mechanism.…”

Section: Introductionmentioning

confidence: 99%

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Perifosine-mediated Akt inhibition in neuroendocrine tumor cells: role of specific Akt isoforms

Zitzmann

Vlotides²,

Brand³

et al. 2012

Endocrine-Related Cancer

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The majority of neuroendocrine tumors (NETs) of the gastroenteropancreatic system show aberrant Akt activity. Several inhibitors of the phosphoinositide 3-kinase (PI(3)K)-Akt-mTOR signaling pathway are currently being evaluated in clinical phase II and III studies for the treatment of NETs with promising results. However, the molecular mechanisms and particularly the role of different Akt isoforms in NET signaling are not fully understood. In this study, we examine the effect of Akt inhibition on NET cells of heterogeneous origin. We show that the Akt inhibitor perifosine effectively inhibits Akt phosphorylation and cell viability in human pancreatic (BON1), bronchus (NCI-H727), and midgut (GOT1) NET cells. Perifosine treatment suppressed the phosphorylation of Akt downstream targets such as GSK3a/b, MDM2, and p70S6K and induced apoptosis. To further investigate the role of individual Akt isoforms for NET cell function, we specifically blocked Akt1, Akt2, and Akt3 via siRNA transfection. In contrast to Akt2 knockdown, knockdown of Akt isoforms 1 and 3 decreased phosphorylation levels of GSK3a/b, MDM2, and p70S6K and suppressed NET cell viability and colony-forming capacity. The inhibitory effect of simultaneous downregulation of Akt1 and Akt3 on tumor cell viability was significantly stronger than that caused by downregulation of all Akt isoforms, suggesting a particular role for Akt1 and Akt3 in NET signaling. Akt3 siRNA-induced apoptosis while all three isoform-specific siRNAs impaired BON1 cell invasion. Together, our data demonstrate potent antitumor effects of the panAkt inhibitor perifosine on NET cells in vitro and suggest that selective targeting of Akt1 and/or Akt3 might improve the therapeutic potential of Akt inhibition in NET disease.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

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Perifosine-mediated Akt inhibition in neuroendocrine tumor cells: role of specific Akt isoforms

Zitzmann

Vlotides²,

Brand³

et al. 2012

Endocrine-Related Cancer

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“…So far, only a few preclinical reports, mainly based on in vitro experiments, have appeared. [5][6][7][8] In this context, the objective of our study was to evaluate, in vitro and in vivo, the effects of rapamycin on intestinal endocrine tumor cell lines, representative of the human highgrade endocrine carcinomas that are putative targets for treatment by rapamycin analogues. 19 Our results suggest that rapamycin may act through several coordinated mechanisms.…”

Section: Discussionmentioning

confidence: 99%

“…Only four recent works reported on the effects of rapamycin or its analog RAD001 on endocrine cell lines on the basis of in vitro experiments. [5][6][7][8] To gain further insight into the mechanisms of antitumor activity of rapalogues in GEP neuroendocrine tumors, we designed an experimental study based on two murine endocrine cell lines, STC-1 and GLUTag, which mimic the behavior of human high-grade endocrine carcinoma. After establishing the in vitro effects of rapamycin, we attempted to evaluate in vivo, using a preclinical animal model of intrahepatic dissemination developed in the laboratory, 9 the relative contributions of the antiproliferative, proapoptotic, and antiangiogenic effects that may be exerted by rapamycin alone or in combination with the PI3K inhibitor LY294002, which targets the same pathway.…”

mentioning

confidence: 99%

Targeting the PI3K/mTOR Pathway in Murine Endocrine Cell Lines

Couderc

Poncet

Villaume

et al. 2011

The American Journal of Pathology

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The mammalian target of rapamycin (mTOR) inhibitors, such as rapalogues, are a promising new tool for the treatment of metastatic gastroenteropancreatic endocrine tumors. However, their mechanisms of action remain to be established. We used two murine intestinal endocrine tumoral cell lines, STC-1 and GLUTag, to evaluate the antitumor effects of rapamycin in vitro and in vivo in a preclinical model of liver endocrine metastases. In vitro, rapamycin inhibited the proliferation of cells in the basal state and after stimulation by insulin-like growth factor-1. Simultaneously, p70S6 kinase and 4EBP1 phosphorylation was inhibited. In vivo, rapamycin substantially inhibited the intrahepatic growth of STC-1 cells, irrespectively of the timing of its administration and even when the treatment was administered after cell intrahepatic engraftment. In addition, treated animals had significantly prolonged survival (mean survival time: 47.7 days in treated animals versus 31.8 days in controls) and better clinical status. Rapamycin treatment was associated with a significant decrease in mitotic index and in intratumoral vascular density within STC-1 tumors. Furthermore, the antitumoral effect obtained after treatment with a combination of rapamycin and phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 was more significant than with rapamycin alone in both cell lines. Our results suggest that the antitumor efficacy of rapamycin in neuroendocrine tumors results from a combination of antiproliferative and antiangiogenic effects. Interestingly, a more potent antitumor efficiency could be obtained by simultaneously targeting several levels of the PI3K/ mTOR pathway.

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The pivotal role of mammalian target of rapamycin inhibition in the treatment of patients with neuroendocrine tumors

Phan

Dave

2016

Cancer Medicine

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Significant advances have been made toward understanding the biology of neuroendocrine tumors (NET) in terms of defining prognosis and improving clinical management; however, many unmet needs remain. The treatment landscape for NET has evolved, with the approval of the targeted agents everolimus and sunitinib for the treatment of advanced pancreatic NET in 2011 followed by the approval of everolimus for the treatment of advanced nonfunctional gastrointestinal and lung NET in 2016. Mammalian target of rapamycin (mTOR) and components of the mTOR pathway play pivotal roles in NET pathogenesis. Effects of the mTOR inhibitor everolimus have been well documented in preclinical and clinical studies, both as monotherapy and combination therapy. mTOR inhibition as backbone therapy within the NET treatment landscape is a focus of continuing research, which includes evaluation of the growing armamentarium of approved and investigational agents as potential combination partners. Data evaluating the clinical benefits of agents targeting mTOR and related pathways (alone and in combination) in the treatment of patients with NET continue to increase. Many of the findings to date are encouraging.

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Compensatory activation of Akt in response to mTOR and Raf inhibitors – A rationale for dual-targeted therapy approaches in neuroendocrine tumor disease

Cited by 118 publications

References 32 publications

Perifosine-mediated Akt inhibition in neuroendocrine tumor cells: role of specific Akt isoforms

Perifosine-mediated Akt inhibition in neuroendocrine tumor cells: role of specific Akt isoforms

Targeting the PI3K/mTOR Pathway in Murine Endocrine Cell Lines

The pivotal role of mammalian target of rapamycin inhibition in the treatment of patients with neuroendocrine tumors

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