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

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Abstract

Purpose

Anaplastic 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.

Methods

ATC 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.

Results

Cell 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.

Conclusions

This 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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Acknowledgements

The authors are thankful for the collaboration of the Endocrinology, Pathology and Surgery Departments from Instituto Português de Oncologia de Lisboa Francisco Gentil E.P.E. (IPOLFG), Lisboa, Portugal.

Funding

This work was funded by Associação de Endocrinologia Oncológica (AEO) and iNOVA4Health Research Unit (LISBOA-01-0145-FEDER-007344), which is cofunded by Fundação para a Ciência e Tecnologia/Ministério da Ciência e do Ensino Superior, through national funds, and by FEDER under the PT2020 Partnership Agreement. Marta Pojo was supported by Núcleo Regional Sul da Liga Portuguesa Contra o Cancro (NRS-LPCC). Inês J. Marques was a recipient of a PhD fellowship from the PhD Programme ProRegeM (Mechanisms of Disease and Regenerative Medicine) approved by Fundação para a Ciência e Tecnologia—PD/BD/108086/2015.

Author information

Author notes

  1. S. Lopes-Ventura and M. Pojo contributed equally to this work.

Authors and Affiliations

  1. Unidade de Investigação em Patobiologia Molecular (UIPM), Instituto Português de Oncologia de Lisboa Francisco Gentil E.P.E., Rua Prof. Lima Basto, 1099-023, Lisbon, Portugal

    S. Lopes-Ventura, M. Pojo, A. T. Matias, M. M. Moura, I. J. Marques, V. Leite & B. M. Cavaco

  2. Serviço de Endocrinologia, Instituto Português de Oncologia de Lisboa Francisco Gentil E.P.E., Rua Prof. Lima Basto, 1099-023, Lisbon, Portugal

    V. Leite

  3. Centro de Estudos de Doenças Crónicas (CEDOC), Rua Câmara Pestana nº 6, 6-A, Edifício CEDOC II, 1150-082, Lisbon, Portugal

    I. J. Marques

  4. NOVA Medical School, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, 1169-056, Lisbon, Portugal

    I. J. Marques & V. Leite

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  1. S. Lopes-Ventura
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  2. M. Pojo
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Correspondence to B. M. Cavaco.

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Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This study was approved by the Ethical Committee of Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG). This article does not contain any studies with human subjects or animal experiments performed by any of the authors.

Informed consent

Informed consent was previously obtained from patients to establish in-house derived cell lines.

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Lopes-Ventura, S., Pojo, M., Matias, A.T. et al. The efficacy of HRAS and CDK4/6 inhibitors in anaplastic thyroid cancer cell lines. J Endocrinol Invest 42, 527–540 (2019). https://doi.org/10.1007/s40618-018-0947-4

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  • DOI: https://doi.org/10.1007/s40618-018-0947-4

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