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Dual inhibition of HDAC and EGFR signaling with CUDC-101 induces potent suppression of tumor growth and metastasis in anaplastic thyroid cancer.

Zhang L, Zhang Y, Mehta A, Boufraqech M, Davis S, Wang J, Tian Z, Yu Z, Boxer MB, Kiefer JA, Copland JA, Smallridge RC, Li Z, Shen M, Kebebew E - Oncotarget (2015)

Bottom Line: The anticancer effect of CUDC-101 was associated with increased expression of p21 and E-cadherin, and reduced expression of survivin, XIAP, β-catenin, N-cadherin, and Vimentin.In an in vivo mouse model of metastatic ATC, CUDC-101 inhibited tumor growth and metastases, and significantly prolonged survival.Response to CUDC-101 treatment in vivo was associated with increased histone 3 acetylation and reduced survivin expression.

View Article: PubMed Central - PubMed

Affiliation: Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

ABSTRACT
Anaplastic thyroid cancer (ATC) is one of the most lethal human malignancies that currently has no effective therapy. We performed quantitative high-throughput screening (qHTS) in three ATC cell lines using 3,282 clinically approved drugs and drug candidates, and identified 100 active agents. Enrichment analysis of active compounds showed that inhibitors of EGFR and histone deacetylase (HDAC) were most active. Of these, the first-in-class dual inhibitor of EGFR, HER2 and HDACs, CUDC-101, had the highest efficacy and lower IC50 than established drugs. We validated that CUDC-101 inhibited cellular proliferation and resulted in cell death by inducing cell cycle arrest and caspase-dependent apoptosis. CUDC-101 also inhibited cellular migration in vitro. Mechanistically, CUDC-101 inhibited MAPK signaling and histone deacetylation in ATC cell lines with multiple driver mutations present in human ATC. The anticancer effect of CUDC-101 was associated with increased expression of p21 and E-cadherin, and reduced expression of survivin, XIAP, β-catenin, N-cadherin, and Vimentin. In an in vivo mouse model of metastatic ATC, CUDC-101 inhibited tumor growth and metastases, and significantly prolonged survival. Response to CUDC-101 treatment in vivo was associated with increased histone 3 acetylation and reduced survivin expression. Our findings provide a preclinical basis to evaluate CUDC-101 therapy in ATC.

No MeSH data available.


Related in: MedlinePlus

Results of qHTS in ATC cell linesEnrichment analysis was performed. The enrichment ratio (green, right Y-axis) represents the number of active drugs (red) vs. total drugs (blue, left Y-axis) by drug mode of action. An enrichment score of 0.7 was used as a cutoff.
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Figure 1: Results of qHTS in ATC cell linesEnrichment analysis was performed. The enrichment ratio (green, right Y-axis) represents the number of active drugs (red) vs. total drugs (blue, left Y-axis) by drug mode of action. An enrichment score of 0.7 was used as a cutoff.

Mentions: Molecular heterogeneity among and within tumors is one of the major reasons that the efficacy of anticancer drugs is restricted to only a small subset of patients. To search for new therapies that are effective for broad groups of patients, we performed the drug library screening in three different ATC cell lines with distinct genetic background, 8505c, C-643 and SW-1736. Since TP53 and the genes involved in PI3K/AKT/mTOR and MAPK pathways are frequently mutated in ATC, we first examined the mutation status of genes involved in these pathways. As summarized in Table 1, all three cell lines displayed TP53-inactivating mutations, as well as mutations in EGFR, MET, BRAF, RAS, PI3K, PTEN, and mTOR, suggesting that these cell lines are representative of human ATC. Thus, we used these three cell lines for the qHTS of the 3,282-compound library, and identified 100 compounds that were pan-active in the three ATC cell lines (Supplementary Table S1). To identify the top-ranking drug targets active against ATC cells, we performed enrichment analysis by mode-of-drug action on target classes that have at least five drugs in each class, and demonstrated that inhibitors of HDAC, aurora kinase, mTOR, and EGFR were the most active drug categories (Figure 1).


Dual inhibition of HDAC and EGFR signaling with CUDC-101 induces potent suppression of tumor growth and metastasis in anaplastic thyroid cancer.

Zhang L, Zhang Y, Mehta A, Boufraqech M, Davis S, Wang J, Tian Z, Yu Z, Boxer MB, Kiefer JA, Copland JA, Smallridge RC, Li Z, Shen M, Kebebew E - Oncotarget (2015)

Results of qHTS in ATC cell linesEnrichment analysis was performed. The enrichment ratio (green, right Y-axis) represents the number of active drugs (red) vs. total drugs (blue, left Y-axis) by drug mode of action. An enrichment score of 0.7 was used as a cutoff.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4496203&req=5

Figure 1: Results of qHTS in ATC cell linesEnrichment analysis was performed. The enrichment ratio (green, right Y-axis) represents the number of active drugs (red) vs. total drugs (blue, left Y-axis) by drug mode of action. An enrichment score of 0.7 was used as a cutoff.
Mentions: Molecular heterogeneity among and within tumors is one of the major reasons that the efficacy of anticancer drugs is restricted to only a small subset of patients. To search for new therapies that are effective for broad groups of patients, we performed the drug library screening in three different ATC cell lines with distinct genetic background, 8505c, C-643 and SW-1736. Since TP53 and the genes involved in PI3K/AKT/mTOR and MAPK pathways are frequently mutated in ATC, we first examined the mutation status of genes involved in these pathways. As summarized in Table 1, all three cell lines displayed TP53-inactivating mutations, as well as mutations in EGFR, MET, BRAF, RAS, PI3K, PTEN, and mTOR, suggesting that these cell lines are representative of human ATC. Thus, we used these three cell lines for the qHTS of the 3,282-compound library, and identified 100 compounds that were pan-active in the three ATC cell lines (Supplementary Table S1). To identify the top-ranking drug targets active against ATC cells, we performed enrichment analysis by mode-of-drug action on target classes that have at least five drugs in each class, and demonstrated that inhibitors of HDAC, aurora kinase, mTOR, and EGFR were the most active drug categories (Figure 1).

Bottom Line: The anticancer effect of CUDC-101 was associated with increased expression of p21 and E-cadherin, and reduced expression of survivin, XIAP, β-catenin, N-cadherin, and Vimentin.In an in vivo mouse model of metastatic ATC, CUDC-101 inhibited tumor growth and metastases, and significantly prolonged survival.Response to CUDC-101 treatment in vivo was associated with increased histone 3 acetylation and reduced survivin expression.

View Article: PubMed Central - PubMed

Affiliation: Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

ABSTRACT
Anaplastic thyroid cancer (ATC) is one of the most lethal human malignancies that currently has no effective therapy. We performed quantitative high-throughput screening (qHTS) in three ATC cell lines using 3,282 clinically approved drugs and drug candidates, and identified 100 active agents. Enrichment analysis of active compounds showed that inhibitors of EGFR and histone deacetylase (HDAC) were most active. Of these, the first-in-class dual inhibitor of EGFR, HER2 and HDACs, CUDC-101, had the highest efficacy and lower IC50 than established drugs. We validated that CUDC-101 inhibited cellular proliferation and resulted in cell death by inducing cell cycle arrest and caspase-dependent apoptosis. CUDC-101 also inhibited cellular migration in vitro. Mechanistically, CUDC-101 inhibited MAPK signaling and histone deacetylation in ATC cell lines with multiple driver mutations present in human ATC. The anticancer effect of CUDC-101 was associated with increased expression of p21 and E-cadherin, and reduced expression of survivin, XIAP, β-catenin, N-cadherin, and Vimentin. In an in vivo mouse model of metastatic ATC, CUDC-101 inhibited tumor growth and metastases, and significantly prolonged survival. Response to CUDC-101 treatment in vivo was associated with increased histone 3 acetylation and reduced survivin expression. Our findings provide a preclinical basis to evaluate CUDC-101 therapy in ATC.

No MeSH data available.


Related in: MedlinePlus