mTOR Pathway Overactivation in BRAF Mutated Papillary Thyroid Carcinoma

Faustino, Alexandra; Couto, Joana; Pópulo, Helena; Rocha, Ana Sofia; Pardal, Fernando; Cameselle-Teijeiro, José; Lopes, José Manuel; Sobrinho-Simões, Manuel; Soares, Paula

doi:10.1210/jc.2011-2748

Cited by 71 publications

(61 citation statements)

References 38 publications

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“…The combination of PD0325901 and PLX4032 resulted in similar pErk levels to PD0325901 alone. In addition, the decrement in pS6 levels roughly correlated with the degree of pErk suppression, suggesting that Braf V600E -mediated signaling impinges upon the mTOR pathway as has been previously suggested (27,28). We additionally assessed cellular growth of mATC and 8505c cells in response to PLX4032, PD0325901, and the combination of drugs.…”

Section: Combined Mek/braf Inhibition Enhances Efficacy Of Mapk Pathwaymentioning

confidence: 67%

p53 constrains progression to anaplastic thyroid carcinoma in a Braf -mutant mouse model of papillary thyroid cancer

McFadden

Vernon

Santiago

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

135

117

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Anaplastic thyroid carcinoma (ATC) has among the worst prognoses of any solid malignancy. The low incidence of the disease has in part precluded systematic clinical trials and tissue collection, and there has been little progress in developing effective therapies. v-raf murine sarcoma viral oncogene homolog B (BRAF) and tumor protein p53 (TP53) mutations cooccur in a high proportion of ATCs, particularly those associated with a precursor papillary thyroid carcinoma (PTC). To develop an adult-onset model of BRAF-mutant ATC, we generated a thyroid-specific CreER transgenic mouse. We used a Cre-regulated Braf V600E mouse and a conditional Trp53 allelic series to demonstrate that p53 constrains progression from PTC to ATC. Gene expression and immunohistochemical analyses of murine tumors identified the cardinal features of human ATC including loss of differentiation, local invasion, distant metastasis, and rapid lethality. We used small-animal ultrasound imaging to monitor autochthonous tumors and showed that treatment with the selective BRAF inhibitor PLX4720 improved survival but did not lead to tumor regression or suppress signaling through the MAPK pathway. The combination of PLX4720 and the mapk/Erk kinase (MEK) inhibitor PD0325901 more completely suppressed MAPK pathway activation in mouse and human ATC cell lines and improved the structural response and survival of ATC-bearing animals. This model expands the limited repertoire of autochthonous models of clinically aggressive thyroid cancer, and these data suggest that small-molecule MAPK pathway inhibitors hold clinical promise in the treatment of advanced thyroid carcinoma.vemurafenib | anaplastic thyroid cancer | MEK inhibitor | genetically-engineered mouse model

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Section: Combined Mek/braf Inhibition Enhances Efficacy Of Mapk Pathwaymentioning

confidence: 67%

p53 constrains progression to anaplastic thyroid carcinoma in a Braf -mutant mouse model of papillary thyroid cancer

McFadden

Vernon

Santiago

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

135

117

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“…Accordingly, the BRAF V600E mutation has been linked to enhanced mTOR signaling via regulation of the protein kinase B (Akt) pathway [41]. In addtion, other studies indicate that BRAF V600E mutant cells have a dysfunctional tumor suppressor liver kinase B1 (LKB1)-adenosine monophosphate-activated protein kinase-mTOR signaling [42,43], and a positive association between the BRAF V600E mutation and mTOR pathway activation has been reported in BRAF-associated papillary thyroid carcinoma [44]. Thus, BRAF-induced phosphorylation of LKB1 may represent a possible additional mechanism contributing to mTOR activation in BRAF V600E-mutated GNTs, possibly mTOR Signaling Pathway and Malformations Overactivation of the mTOR signaling in glioneuronal tumors (GNT), focal cortical dysplasia (FCD) IIb, and hemimegalencephaly (HME), as well as tubers in tuberous sclerosis complex (TSC), suggests a pathogenic link between these malformations and reflects a spectrum of disorders of mTOR signaling (mTORopathies; see text).…”

Section: Pathogenesis and Molecular Geneticsmentioning

confidence: 99%

Epilepsy Related to Developmental Tumors and Malformations of Cortical Development

Aronica

Crino

2014

Neurotherapeutics

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“…As stated earlier, alterations in the PI3K̸Akt̸mTOR pathway in ATC was not a major genetic abnormality, compared to B-Raf-or Ras-mediated pathway. Farstino et al (22) suggested the possible mechanism of LKB1-mediated mTOR pathway upregulation in thyroid carcinoma harboring the B-Raf mutation. Dual inhibition of the Raf/Ras̸MEK and PI3K̸Akt̸mTOR pathways was attempted, with promising preclinical results (23).…”

Section: Discussionmentioning

confidence: 99%

Significant cytostatic effect of everolimus on a gefitinib-resistant anaplastic thyroid cancer cell line harboring PI3KCA gene mutation

Onoda

Nakamura

Aomatsu

et al. 2015

Molecular and Clinical Oncology

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Abstract. We previously demonstrated the efficacy of gefitinib, a tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR), on an anaplastic thyroid cancer (ATC) cell line. We also observed that gefitinib was not effective in regulating cell growth in a different ATC cell line that exhibited an altered EGFR-initiated signal transduction pathway. In the present study, we attempted to regulate the downstream effector of EGFR-Akt-mammalian target of rapamycin (mTOR) pathway by an mTOR inhibitor, everolimus. A total of 8 ATC cell lines were employed, 7 of which were established in our institute. OCUT-2 was known to carry a mutation in the phosphoinositide-3-kinase, catalytic, α polypeptide gene (PI3KCA) and to be gefitinib-resistant, whereas ACT-1 exhibited a remarkable growth arrest by gefitinib. All the cell lines were tested for the cytotoxic effect of everolimus. The mechanisms of cellular toxicity were investigated by EGFR stimulation, cell cycle and concurrent exposure to paclitaxel. In OCUT-2, but not in any of the other cell lines, everolimus achieved a significant growth inhibition (inhibition of 30 and 50% was achieved by concentrations of 0.8 and 5 nM, respectively). The growth in OCUT-2 was inhibited by everolimus, even with concordant EGFR stimulation. This effect was demonstrated by a G2M cell cycle arrest. An additive effect of everolimus onto the cytotoxic effect of paclitaxel was demonstrated at a dose of 1-2 nM. A significant growth inhibitory effect of everolimus on the gefitinib-resistant ATC cell line was demonstrated, suggesting a possible correlation between the efficacy of everolimus and PI3KCA gene mutation and the significance of molecular-targeted therapy in the management of ATC.

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mTOR Pathway Overactivation in BRAF Mutated Papillary Thyroid Carcinoma

Cited by 71 publications

References 38 publications

p53 constrains progression to anaplastic thyroid carcinoma in a Braf -mutant mouse model of papillary thyroid cancer

p53 constrains progression to anaplastic thyroid carcinoma in a Braf -mutant mouse model of papillary thyroid cancer

Epilepsy Related to Developmental Tumors and Malformations of Cortical Development

Significant cytostatic effect of everolimus on a gefitinib-resistant anaplastic thyroid cancer cell line harboring PI3KCA gene mutation

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