Oncogenic Kras Requires Simultaneous PI3K Signaling to Induce ERK Activation and Transform Thyroid Epithelial Cells <i>In vivo</i>

Miller, Kelly A.; Yeager, Nicole; Baker, Kristen; Liao, Xiao Hui; Refetoff, Samuel; Cristofano, Antonio Di

doi:10.1158/0008-5472.can-09-0024

Cited by 118 publications

(133 citation statements)

References 26 publications

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“…Interestingly, these two pathways are often activated in combination specifically in anaplastic thyroid carcinomas (Liu et al, 2008;Miller et al, 2009). This is also consistent with the previous observation of only a mild miR-21 overexpression in papillary thyroid cancers carrying activating mutations of Braf, which in turn specifically activate the MAPK pathway, while being unable to activate the PI3K pathway (He et al, 2005).…”

Section: Discussionsupporting

confidence: 91%

Upregulation of miR-21 by Ras in vivo and its role in tumor growth

et al. 2010

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miR-21 is a microRNA (miRNA) frequently overexpressed in human cancers. Here we show that miR-21 is upregulated both in vitro and in vivo by oncogenic Ras, thus linking this miRNA to one of the most frequently activated oncogenes in human cancers. Ras regulation of miR-21 occurs with a delayed kinetic and requires at least two Ras downstream pathways. A screen of human thyroid cancers and non-small-cell lung cancers for the expression of miR-21 reveals that it is overexpressed mainly in anaplastic thyroid carcinomas, the most aggressive form of thyroid cancer, whereas in lung its overexpression appears to be inversely correlated with tumor progression. We also show that a LNA directed against miR-21 slows down tumor growth in mice. Consistently, a search for mRNAs downregulated by miR-21 shows an enrichment for mRNAs encoding cell cycle checkpoints regulators, suggesting an important role for miR-21 in oncogenic Ras-induced cell proliferation.

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Section: Discussionsupporting

confidence: 91%

Upregulation of miR-21 by Ras in vivo and its role in tumor growth

et al. 2010

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“…In conclusion, extensive reports suggest a constitutive activation of the MAPK signalling activation in thyroid cancers, and PI-3K activation might be an essential factor for tumorigenesis (Miller et al, 2009). However, the relative importance of the PI-3K versus the MAPK signalling pathway is not fully elucidated since PI-3K activation can in turn facilitate MAPK activation (Miller et al, 2009).…”

Section: Resultsmentioning

confidence: 91%

“…However, the relative importance of the PI-3K versus the MAPK signalling pathway is not fully elucidated since PI-3K activation can in turn facilitate MAPK activation (Miller et al, 2009). Additional alterations are required to go further in the dedifferentiation process.…”

Section: Resultsmentioning

confidence: 99%

“…The striking similitude of the conditions we defined as necessary for thyroid cell growth i.e. the necessary stimulation of both the TSH-cAMP or the EGF-MAPK pathway and of the IGF-I/insulin-PI3Kinase pathway (Roger et al, 1987;Coulonval et al, 2000;Vandeput et al, 2003) to the conditions of thyroid carcinoma induction in mice (Miller et al, 2009) illustrates a posteriori the power of this approach.…”

Section: Tumors and Their Modelsmentioning

confidence: 92%

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Signal transduction in the human thyrocyte and its perversion in thyroid tumors

Roger

Staveren

Coulonval

et al. 2010

Molecular and Cellular Endocrinology

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The study of normal signal transduction pathways regulating the proliferation and differentiation of a cell type allows to predict and to understand the perversions of these pathways which lead to tumorigenesis. In the case of the human thyroid cell, three cascades are mostly involved in tumorigenesis:the TSH receptor-cyclic AMP cascade, the constitutive activation of which leads to autonomous adenomas and congenital hyperthyroidism.the growth factor-Ras-MAP kinase pathway, whose constitutive activation causes follicular and papillary carcinomas.the PI-3Kinase-PKB pathway, the activity of which is necessary for both pathways and the corresponding tumors.The pathways and genetic events affecting them are described. Caveats in the use of models and the interpretation of results are formulated and the still pending questions are outlined.

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“…As such, combined inhibition of PI3K and RAS/MAPK pathways has had success preclinically. In vivo studies in LSL-Kras G12D lung cancer mice (29), breast cancer MCF7 xenografts (34), PTEN-deleted/Nxk3.1-deleted androgen-independent prostate cancer-bearing mice (35), and TPO-Kras G12D ;Pten del thyroid cancer mice (36) have each shown improved efficacy with combined PI3K and MEK pathway inhibition.…”

Section: Discussionmentioning

confidence: 99%

In Vivo Activity of Combined PI3K/mTOR and MEK Inhibition in a KrasG12D;Pten Deletion Mouse Model of Ovarian Cancer

Kinross

Brown

Kleinschmidt

et al. 2011

Molecular Cancer Therapeutics

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The phosphatidylinositol 3-kinase (PI3K)/Akt pathway is commonly dysregulated in human cancer, making it an attractive target for novel anticancer therapeutics. We have used a mouse model of ovarian cancer generated by Kras G12D activation and Pten deletion in the ovarian surface epithelium for the preclinical assessment of a novel PI3K/mTOR inhibitor PF-04691502. To enable higher throughput studies, we developed an orthotopic primary transplant model from these mice and evaluated therapeutic response to PF-04691502 using small-animal ultrasound and FDG-PET imaging. PF-04691502 inhibited tumor growth at 7 days by 72% AE 9. FDG-PET imaging revealed that PF-04691502 reduced glucose metabolism dramatically, suggesting FDG-PET may be exploited as an imaging biomarker of target inhibition by PF-04691502. Tissue biomarkers of PI3K/mTOR pathway activity, p-AKT (S473), and p-RPS6 (S240/244), were also dramatically inhibited following PF-04691502 treatment. However, as a single agent, PF-04691502 did not induce tumor regression and the long-term efficacy was limited, with tumor proliferation continuing in the presence of drug treatment. We hypothesized that tumor progression was because of concomitant activation of the mitogenactivated protein kinase pathway downstream of Kras G12D expression promoting cell survival and that the therapeutic effect of PF-04691502 would be enhanced by combinatory inhibition of MEK using PD-0325901. This combination induced striking tumor regression, apoptosis associated with upregulation of Bim and downregulation of Mcl-1, and greatly improved duration of survival. These data suggest that contemporaneous MEK inhibition enhances the cytotoxicity associated with abrogation of PI3K/mTOR signaling, converting tumor growth inhibition to tumor regression in a mouse model of ovarian cancer driven by PTEN loss and mutant K-Ras.

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Oncogenic Kras Requires Simultaneous PI3K Signaling to Induce ERK Activation and Transform Thyroid Epithelial Cells In vivo

Cited by 118 publications

References 26 publications

Upregulation of miR-21 by Ras in vivo and its role in tumor growth

Upregulation of miR-21 by Ras in vivo and its role in tumor growth

Signal transduction in the human thyrocyte and its perversion in thyroid tumors

In Vivo Activity of Combined PI3K/mTOR and MEK Inhibition in a KrasG12D;Pten Deletion Mouse Model of Ovarian Cancer

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