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Updated: Feb 5, 2026
Spontaneous Murine Model of Anaplastic Thyroid Cancer
Published on: February 3, 2023
The efficacy of HRAS and CDK4/6 inhibitors in anaplastic thyroid cancer cell lines
S Lopes-Ventura1, M Pojo1, A T Matias1
1Unidade 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.
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.
Insights
Tipifarnib (TIP) and palbociclib (PD) show potential for treating anaplastic thyroid carcinoma (ATC). TIP targets HRAS mutations, while PD affects CDKN2A/B alterations, suggesting personalized ATC therapy based on tumor molecular profile.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Anaplastic thyroid carcinoma (ATC) is a challenging cancer due to its resistance to conventional therapies.
- Genetic mutations in cell cycle and proliferation genes (TP53, RAS, CDKN2A, CDKN2B) are common in ATCs.
- Targeting these deregulated genes presents a potential therapeutic strategy for ATC.
Purpose of the Study:
- To investigate the efficacy of tipifarnib (TIP) in inhibiting HRAS.
- To evaluate the effects of palbociclib (PD) on cyclin D-cyclin-dependent kinase 4/6 (CDK4/6) in ATC cells.
- To determine the potential of TIP and PD as targeted therapies for ATC based on specific genetic alterations.
Main Methods:
- Utilized ATC cell lines with varying mutations in HRAS, CDKN2A, and CDKN2B genes.
- Assessed the cytotoxic effects of TIP and PD using half maximal inhibitory concentration (IC50) values.
- Analyzed the impact of these drugs on cell cycle progression, cell death, and cell proliferation.
Main Results:
- TIP induced G2/M phase cell cycle arrest, cell death, and reduced viability in HRAS-mutated ATC cells.
- PD caused G0/G1 phase cell cycle arrest and cell death in ATC cells with CDKN2A/CDKN2B alterations.
- PD's inhibition of cell viability was more significant in cells with CDKN2A/CDKN2B alterations and/or cyclin D1 overexpression.
Conclusions:
- TIP and PD demonstrate targeted efficacy against specific molecular profiles in ATC.
- These drugs, currently in clinical trials for other cancers, show promise for ATC treatment.
- Tumor molecular profiling is crucial for determining the optimal use of TIP and PD in ATC therapy.
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