Anaplastic thyroid carcinoma: advances in molecular profiling and targeted therapy.

PURPOSE OF REVIEW: Anaplastic thyroid carcinomas (ATCs) are rare cancers with a globally very poor prognosis, because of their immensely aggressive behaviour, resulting in predominantly advanced stage of disease at diagnosis. Response to available therapies is still disappointing. Aim of the present review is to illustrate the diverse new strategies under investigation, to improve the poor outcome of these patients. RECENT FINDINGS: Applying molecular analysis in ATC is unravelling potentially actionable targets of therapy. If a mutation of BRAF V600E is found, a combination of Dabrafenib and Trametinib is the recommended treatment. In the presence of another druggable mutation, a specific targeted therapy may be proposed. In the absence of druggable mutations, immunotherapy is an alternative approach, especially in case of significant PD-L1 expression. SUMMARY: The molecular profiling of tumour samples is elucidating the genetic alterations involved in ATC development, and new preclinical models are under study to define innovative approaches for individualized treatment of such patients. Hopefully this approach could improve ATC prognosis.

Cell cycle deregulation and TP53 and RAS mutations are major events in poorly differentiated and undifferentiated thyroid carcinomas.

BACKGROUND: Anaplastic thyroid carcinomas (ATCs) are among the most lethal malignancies, for which there is no effective treatment. OBJECTIVE: In the present study, we aimed to elucidate the molecular alterations contributing to ATC development and to identify novel therapeutic targets. DESIGN: We profiled the global gene expression of five ATCs and validated differentially expressed genes by quantitative RT-PCR in an independent set of tumors. In a series of 26 ATCs, we searched for pathogenic alterations in genes involved in the most deregulated cellular processes, including the hot spot regions of RAS, BRAF, TP53, CTNNB1 (ß-catenin), and PIK3CA genes, and, for the first time, a comprehensive analysis of components involved in the cell cycle [cyclin-dependent kinase (CDK) inhibitors (CDKI): CDKN1A (p21(CIP1)); CDKN1B (p27(KIP1)); CDKN2A (p14(ARF), p16(INK4A)); CDKN2B (p15(INK4B)); CDKN2C (p18(INK4C))], cell adhesion (AXIN1), and proliferation (PTEN). Mutational analysis was also performed in 22 poorly differentiated thyroid carcinomas (PDTCs). RESULTS: Expression profiling revealed that ATCs were characterized by the underexpression of epithelial components and the up regulation of mesenchymal markers and genes from TGF-ß pathway, as well as, the overexpression of cell cycle-related genes. In accordance, the up regulation of the SNAI2 gene, a TGF-ß-responsive mesenchymal factor, was validated. CDKN3, which prevents the G1/S transition, was significantly up regulated in ATCs and PDTCs and aberrantly spliced in ATCs. Mutational analysis showed that most mutations were present in TP53 (42% of ATCs; 27% of PDTCs) or RAS (31% of ATCs; 18% of PDTCs). TP53 and RAS alterations showed evidence of mutual exclusivity (P = .0354). PIK3CA, PTEN, and CDKI mutations were present in 14%-20% of PDTCs, and in 10%-14% of ATCs. BRAF, CTNNB1, and AXIN1 mutations were rarely detected. CONCLUSION: Overall, this study identified crucial roles for TP53, RAS, CDKI, and TGF-ß pathway, which may represent feasible therapeutic targets for ATC and PDTC treatment.