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Updated: Oct 15, 2025
Spontaneous Murine Model of Anaplastic Thyroid Cancer
Published on: February 3, 2023
Synergistic effect of metformin and vemurufenib (PLX4032) as a molecular targeted therapy in anaplastic thyroid
Latha Durai1, Soundharya Ravindran1, Krishnamurthy Arvind2
1Department of Preventive Oncology (Research), Cancer Institute, Adyar, Chennai, India.
Background:
Survival rate of patients affected with anaplastic thyroid carcinoma (ATC) is less than 5% with current treatment. In ATC, BRAFV600E mutation is the major mutation that results in the transformation of normal cells in to an undifferentiated cancer cells via aberrant molecular signaling mechanisms. Although vemurufenib is a selective oral drug for the BRAFV600E mutant kinase with a response rate of nearly 50% in metastatic melanoma, our study has showed resistance to this drug in ATC. Hence the rationale of the study is to explore combinational therapeutic effect to improve the efficacy of vemurafenib along with metformin. Metformin, a diabetic drug is an AMPK activator and has recently proved to be involved in preventing or treating several types of cancer.
Methods And Results:
Using iGEMDock software, a protein-ligand interaction was successful between Metformin and TSHR (receptor present in the thyroid follicular cells). Our study demonstrates that combination of vemurufenib with metformin has synergistic anti-cancer effects which was evaluated through MTT assay (cytotoxicity), colony formation assay (antiproliferation evaluation) and suppressed the progression of ATC cells growth by inducing significant apoptosis, proven by Annexin V-FITC assay (Early Apoptosis Detection). Downregulation of ERK signaling, upregulation of AMPK pathway and precision in epithelial-mesenchymal transition (EMT) pathway which were assessed by RT-PCR and Western blot provide the evidence that the combination of drugs involved in the precision of altered molecular signaling Further our results suggest that Metformin act as a demethylating agent in anaplastic thyroid cancer cells by inducing the expression of NIS and TSHR. Our study for the first time explored cAMP signaling in ATC wherein cAMP signaling is downregulated due to decrease in intracellular cAMP level upon metformin treatment.
Conclusion:
To conclude, our findings demonstrate novel therapeutic targets and treatment strategies for undifferentiated ATC.
Insights
Combining vemurafenib with metformin shows synergistic anti-cancer effects in anaplastic thyroid carcinoma (ATC). This combination targets BRAF V600E mutations and alters molecular signaling, offering new therapeutic strategies for ATC.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Anaplastic thyroid carcinoma (ATC) has a poor survival rate (<5%) with current treatments.
- BRAF V600E mutation drives ATC development through aberrant molecular signaling.
- Vemurafenib, effective in melanoma, shows resistance in ATC, necessitating alternative strategies.
Purpose of the Study:
- To investigate the combinational therapeutic effect of vemurafenib and metformin in ATC.
- To explore the molecular mechanisms underlying the synergistic effects of vemurafenib and metformin.
- To identify novel therapeutic targets and strategies for undifferentiated ATC.
Main Methods:
- Protein-ligand interaction analysis using iGEMDock software.
- In vitro anti-cancer effects evaluated by MTT assay, colony formation assay, and Annexin V-FITC assay.
- Molecular signaling pathway analysis using RT-PCR and Western blot to assess ERK, AMPK, EMT, and cAMP pathways.
Main Results:
- Metformin showed protein-ligand interaction with TSHR.
- The combination of vemurafenib and metformin exhibited synergistic anti-cancer effects, inducing apoptosis and suppressing ATC cell growth.
- Combination therapy led to ERK signaling downregulation, AMPK pathway upregulation, and modulation of EMT.
- Metformin acted as a demethylating agent, increasing NIS and TSHR expression and downregulating cAMP signaling in ATC cells.
Conclusions:
- The combination of vemurafenib and metformin demonstrates significant anti-cancer activity in ATC.
- This combination offers a promising therapeutic strategy by targeting key molecular signaling pathways.
- Findings reveal novel therapeutic targets and treatment approaches for undifferentiated ATC.
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