Disruption of mutated BRAF signaling modulates thyroid cancer phenotype

Hanly, Elyse K.; Rajoria, Shilpi; Darzynkiewicz, Zbigniew; Zhao, Hong; Suriano, Robert; Tuli, Neha; George, Andrea L.; Bednarczyk, Robert B.; Shin, Edward J.; Geliebter, Jan; Tiwari, Raj K.

doi:10.1186/1756-0500-7-187

Cited by 8 publications

(7 citation statements)

References 36 publications

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“…Vemurafenib binds selectively to the active site of BRAFV600E protein, which differs in conformation from wild-type BRAF, and inhibits downstream MAPK signaling [ 7 ]. Short-term treatment with BRAFV600E inhibitors has drastic anti-proliferative effects on mutated thyroid cancer cells including induction of apoptosis [ 8 - 10 ]. The drug vemurafenib has also recently proved to be useful in treating advanced thyroid cancer patients in clinical trials.…”

Section: Introductionmentioning

confidence: 99%

mTOR inhibitors sensitize thyroid cancer cells to cytotoxic effect of vemurafenib

et al. 2015

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Section: Introductionmentioning

confidence: 99%

mTOR inhibitors sensitize thyroid cancer cells to cytotoxic effect of vemurafenib

et al. 2015

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“…Since development of resistance appeared to be mediated through mechanisms involved in ERK signaling, we analyzed expression of key effector molecules, ERK and mTOR. We noted inhibition of phosphorylation of these molecules in normal BCPAP cells in response to 24 hour VMR treatment in a previous study [ 16 ]. When comparing expression levels of phosphorylated signaling proteins among cell lines, we found that the resistant BCPAP cells expressed a remarkably higher amount of phospho-ERK compared to normal BCPAP (Figure 4 ).…”

Section: Resultsmentioning

confidence: 69%

“…Presence of the BRAFV600E mutation has been correlated with recurrence, resistance to radioiodine, and increased mortality [ 3 , 10 – 13 ]. Inhibition of BRAFV600E kinase with VMR within thyroid cancer cells has been shown to inhibit cell proliferation and induce apoptosis [ 14 – 16 ].…”

Section: Introductionmentioning

confidence: 99%

Hyperactive ERK and persistent mTOR signaling characterize vemurafenib resistance in papillary thyroid cancer cells

et al. 2015

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Clinical studies evaluating targeted BRAFV600E inhibitors in advanced thyroid cancer patients are currently underway. Vemurafenib (BRAFV600E inhibitor) monotherapy has shown promising results thus far, although development of resistance is a clinical challenge. The objective of this study was to characterize development of resistance to BRAFV600E inhibition and to identify targets for effective combination therapy. We created a line of BCPAP papillary thyroid cancer cells resistant to vemurafenib by treating with increasing concentrations of the drug. The resistant BCPAP line was characterized and compared to its sensitive counterpart with respect to signaling molecules thought to be directly related to resistance. Expression and phosphorylation of several critical proteins were analyzed by Western blotting and dimerization was evaluated by immunoprecipitation. Resistance to vemurafenib in BCPAP appeared to be mediated by constitutive overexpression of phospho-ERK and by resistance to inhibition of both phospho-mTOR and phospho-S6 ribosomal protein after vemurafenib treatment. Expression of potential alternative signaling molecule, CRAF, was not increased in the resistant line, although formation of CRAF dimers appeared increased. Expression of membrane receptors HER2 and HER3 was greatly amplified in the resistant cancer cells. Papillary thyroid cancer cells were capable of overcoming targeted BRAFV600E inhibition by rewiring of cell signal pathways in response to prolonged vemurafenib therapy. Our study suggests that in vitro culture of cancer cells may be useful in assessing molecular resistance pathways. Potential therapies in advanced thyroid cancer patients may combine vemurafenib with inhibitors of CRAF, HER2/HER3, ERK, and/or mTOR to delay or abort development of resistance.

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“…In particular, interleukin-1 has dual roles of anti-tumor and pro-tumor [43]. Positive regulation of MAP kinase activity and metalloendopeptidase activity are thought to be associated with thyroid cancer [44,45]. This is a validation of the major carcinogenic event of PTC is the activation of MAPK.…”

Section: Discussionmentioning

confidence: 99%

Identification of hub genes in papillary thyroid carcinoma: robust rank aggregation and weighted gene co-expression network analysis

et al. 2020

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Background: Papillary thyroid carcinoma (PTC), which is the most common endocrine malignancy, has been steadily increasing worldwide in incidence over the years, while mechanisms underlying the pathogenesis and diagnostic for PTC are incomplete. The purpose of this study is to identify potential biomarkers for diagnosis of PTC, and provide new insights into pathogenesis of PTC.Methods: Based on weighted gene co-expression network analysis, Robust Rank Aggregation, functional annotation, GSEA and DNA methylation, were employed for investigating potential biomarkers for diagnosis of PTC.Results: Black and turquoise modules were identified in the gene co-expression network constructed by 1807 DEGs that from 6 eligible gene expression profiles of Gene Expression Omnibus database based on Robust Rank Aggregation and weighted gene co-expression network analysis. Hub genes were significantly down-regulated and the expression levels of the hub genes were different in different stages in hub gene verification. ROC curves indicated all hub genes had good diagnostic value for PTC (except for ABCA6 AUC = 89.5%, the 15 genes with AUC > 90%). Methylation analysis showed that hub gene verification ABCA6, ACACB, RMDN1 and TFPI were identified as differentially methylated genes, and the decreased expression level of these genes may relate to abnormal DNA methylation. Moreover, the expression levels of 8 top hub genes were correlated with tumor purity and tumor-infiltrating immune cells. These findings, including functional annotations and GSEA provide new insights into pathogenesis of PTC. Conclusions:The hub genes and methylation of hub genes may as potential biomarkers provide new insights for diagnosis of PTC, and all these findings may be the direction to study the mechanisms underlying of PTC in the future.

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Disruption of mutated BRAF signaling modulates thyroid cancer phenotype

Cited by 8 publications

References 36 publications

mTOR inhibitors sensitize thyroid cancer cells to cytotoxic effect of vemurafenib

mTOR inhibitors sensitize thyroid cancer cells to cytotoxic effect of vemurafenib

Hyperactive ERK and persistent mTOR signaling characterize vemurafenib resistance in papillary thyroid cancer cells

Identification of hub genes in papillary thyroid carcinoma: robust rank aggregation and weighted gene co-expression network analysis

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