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The efficacy of HRAS and CDK4/6 inhibitors in anaplastic thyroid cancer cell lines

Authors
  • Lopes-Ventura, S.1
  • Pojo, M.1
  • Matias, A. T.1
  • Moura, M. M.1
  • Marques, I. J.1, 2, 3
  • Leite, V.1, 4, 3
  • Cavaco, B. M.1
  • 1 Unidade de Investigação em Patobiologia Molecular (UIPM), Instituto Português de Oncologia de Lisboa Francisco Gentil E.P.E., Rua Prof. Lima Basto, Lisbon, 1099-023, Portugal , Lisbon (Portugal)
  • 2 Centro de Estudos de Doenças Crónicas (CEDOC), Rua Câmara Pestana nº 6, 6-A, Edifício CEDOC II, Lisbon, 1150-082, Portugal , Lisbon (Portugal)
  • 3 Universidade Nova de Lisboa, NOVA Medical School, Faculdade de Ciências Médicas, Lisbon, 1169-056, Portugal , Lisbon (Portugal)
  • 4 Instituto Português de Oncologia de Lisboa Francisco Gentil E.P.E., Rua Prof. Lima Basto, Serviço de Endocrinologia, Lisbon, 1099-023, Portugal , Lisbon (Portugal)
Type
Published Article
Journal
Journal of Endocrinological Investigation
Publisher
Springer-Verlag
Publication Date
Sep 06, 2018
Volume
42
Issue
5
Pages
527–540
Identifiers
DOI: 10.1007/s40618-018-0947-4
Source
Springer Nature
Keywords
License
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Abstract

PurposeAnaplastic thyroid carcinomas (ATCs) are non-responsive to multimodal therapy, representing one of the major challenges in thyroid cancer. Previously, our group has shown that genes involved in cell cycle are deregulated in ATCs, and the most common mutations in these tumours occurred in cell proliferation and cell cycle related genes, namely TP53, RAS, CDKN2A and CDKN2B, making these genes potential targets for ATCs treatment. Here, we investigated the inhibition of HRAS by tipifarnib (TIP) and cyclin D-cyclin-dependent kinase 4/6 (CDK4/6) by palbociclib (PD), in ATC cells.MethodsATC cell lines, mutated or wild type for HRAS, CDKN2A and CDKN2B genes, were used and the cytotoxic effects of PD and TIP in each cell line were evaluated. Half maximal inhibitory concentration (IC50) values were determined for these drugs and its effects on cell cycle, cell death and cell proliferation were subsequently analysed.ResultsCell culture studies demonstrated that 0.1 µM TIP induced cell cycle arrest in the G2/M phase (50%, p < 0.01), cell death, and inhibition of cell viability (p < 0.001), only in the HRAS mutated cell line. PD lowest concentration (0.1 µM) increased significantly cell cycle arrest in the G0/G1 phase (80%, p < 0.05), but only in ATC cell lines with alterations in CDKN2A/CDKN2B genes; additionally, 0.5 µM PD induced cell death. The inhibition of cell viability by PD was more pronounced in cells with alterations in CDKN2A/CDKN2B genes (p < 0.05) and/or cyclin D1 overexpression.ConclusionsThis study suggests that TIP and PD, which are currently in clinical trials for other types of cancer, may play a relevant role in ATC treatment, depending on the specific tumour molecular profile.

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