Dual Inhibition of HDAC and Tyrosine Kinase Signaling Pathways with CUDC-907 Inhibits Thyroid Cancer Growth and Metastases.

Abstract

Purpose: There is currently no standard therapy for anaplastic thyroid cancer (ATC) and poorly differentiated thyroid cancer (PDTC), which account for two-thirds of thyroid cancer-related deaths. Driver mutations in the PI3K/AKT and RAF/RAS/MEK/ERK pathways are common in ATC and PDTC. Histone deacetylases (HDAC) regulate cancer initiation and progression. Our aim was to determine the therapeutic efficacy of simultaneously targeting these pathways in thyroid cancer with a single agent and to evaluate biomarkers of treatment response.Experimental Design: CUDC-907 is a first-in-class compound, functioning as a dual inhibitor of HDACs and the PI3K/AKT pathway. We investigated its antiproliferative effect in vitro and in vivoResults: CUDC-907 significantly inhibited cellular proliferation in thyroid cancer cell lines, induced G2-M arrest with decreased levels of the checkpoint regulators cyclin B1, AURKA, AURKB, PLK1, and increased p21 and p27. Treatment induced apoptosis with increased caspase-3/7 activity and decreased survivin levels and decreased cellular migration and invasion. CUDC-907 treatment caused H3 hyperacetylation and decreased HDAC2 expression. HDAC2 was upregulated in ATC and other thyroid cancer histologic subtypes. CUDC-907 treatment reduced both p-AKT and p-ERK1/2 levels. Finally, CUDC-907 treatment, in a metastatic mouse model of thyroid cancer, showed significant inhibition of growth and metastases, and tumors from treated mice had decreased HDAC2 expression, suggesting that this may be a useful biomarker of response.Conclusions: Dual inhibition of HDAC and the tyrosine kinase signaling pathways with CUDC-907 is a promising treatment strategy for advanced, metastatic thyroid cancer. Clin Cancer Res; 23(17); 5044-54. ©2017 AACR.

• Authors: Shweta Kotian, Lisa Zhang, Myriem Boufraqech, Kelli Gaskins, Sudheer Kumar Gara, Martha Quezado, Naris Nilubol, Electron Kebebew
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 23 Issue 17 Pg. 5044-5054 (Sep 01 2017) ISSN: 1557-3265 [Electronic] United States
• PMID: 28600475 (Publication Type: Journal Article)
• Copyright: ©2017 American Association for Cancer Research.

Chemical References

• CUDC-907
• Histone Deacetylase Inhibitors
• Morpholines
• Protein Kinase Inhibitors
• Pyrimidines
• Protein-Tyrosine Kinases
• Histone Deacetylases

Topics

• Animals
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Histone Deacetylase Inhibitors (administration & dosage)
• Histone Deacetylases (genetics)
• Humans
• Mice
• Morpholines (administration & dosage)
• Neoplasm Metastasis
• Neoplasm Staging
• Protein Kinase Inhibitors (administration & dosage)
• Protein-Tyrosine Kinases (antagonists & inhibitors, genetics)
• Pyrimidines (administration & dosage)
• Signal Transduction (drug effects)
• Thyroid Neoplasms (drug therapy, genetics, pathology)
• Xenograft Model Antitumor Assays