Paradise
Paradise | Life Science Engineering Business Natural Science
  1. You are here:
  2. Home
  3. Journals
  4. Biological Sciences
Paradise

Volume 1 Number 1 2025

Article Contents

RESEARCH ARTICLE   (Open Access)
Contents Vol 1 (1)

Encoded Resistance: Structural Disruption and Signaling Crosstalk Undermine Sorafenib Binding in Mutant VEGFR2-Driven HCC

Tufael1*, Most Farhana Akter2, Md. Robiul Islam2, Md Abu Bakar Siddique3, Nashitha Hassan1, Abdullah Al Numan4, Asika Ayrin Naher4, Md Mahedi Hasan Shabuj4, Amena Khatun Manica5, Bulbul Shaikat6, Tahsin Bin Rabbani6

+ Author Affiliations

Paradise 1 (1) 1-8 https://doi.org/10.25163/paradise.1110427

Submitted: 16 February 2025 Revised: 02 April 2025  Published: 14 April 2025 

Abstract

Background: Hepatocellular carcinoma (HCC) is one of the most aggressive liver cancers, where anti-angiogenic therapies targeting VEGFR2-such as Sorafenib-are widely used. However, the emergence of drug resistance significantly limits long-term treatment success. Despite its clinical relevance, the molecular mechanisms behind this resistance remain inadequately understood. Structural alterations in VEGFR2 and activation of compensatory signaling pathways are suspected contributors.

Aim: This study aimed to evaluate how specific mutations in VEGFR2 affect Sorafenib binding affinity and to elucidate the molecular interactions and signaling disruptions that may underlie drug resistance in HCC.

Methods: The 3D structure of VEGFR2 (PDB ID: 3WZE) and the Sorafenib ligand (CID: 216239) were retrieved and prepared using BIOVIA Discovery Studio. Site-specific mutations (ASP1046→ALA, CYS919→ALA, GLU917→GLN) were introduced into the protein. Molecular docking was conducted using AutoDock Vina in PyRx, followed by interaction analysis using Discovery Studio Visualizer. Additionally, protein-protein interaction (PPI) analysis was performed using the STRING database, and KEGG pathway mapping was employed to explore signaling mechanisms associated with resistance.

Results: Docking results revealed reduced binding affinity between Sorafenib and the mutant VEGFR2 protein, accompanied by disruption of key hydrogen bonding and hydrophobic interactions. PPI and KEGG analyses identified upregulation of angiogenesis-related and alternative signaling pathways, suggesting possible bypass mechanisms that sustain tumor cell survival despite targeted therapy.

Conclusion: Mutations in VEGFR2 may compromise Sorafenib efficacy by altering its binding site and activating alternative molecular pathways. Understanding these resistance mechanisms may support the development of multi-targeted therapeutic strategies for more effective HCC treatment.

Keywords: Hepatocellular carcinoma (HCC), VEGFR2, Sorafenib, Molecular docking, Protein mutation.

References

Balacescu, O., Sur, D., Cainap, C., Visan, S., Cruceriu, D., Manzat-Saplacan, R., Muresan, M.-S., Balacescu, L., Lisencu, C., & Irimie, A. (2018). The Impact of miRNA in Colorectal Cancer Progression and Its Liver Metastases. International Journal of Molecular Sciences, 19(12), 3711. https://doi.org/10.3390/ijms19123711

 

Bou Antoun, N., & Chioni, A.-M. (2023). Dysregulated Signalling Pathways Driving Anticancer Drug Resistance. International Journal of Molecular Sciences, 24(15), 12222. https://doi.org/10.3390/ijms241512222

 

Cabral, L. K. D., Tiribelli, C., & Sukowati, C. H. C. (2020). Sorafenib Resistance in Hepatocellular Carcinoma: The Relevance of Genetic Heterogeneity. Cancers, 12(6), 1576. https://doi.org/10.3390/cancers12061576

 

Dejana, E., Hirschi, K. K., & Simons, M. (2017). The molecular basis of endothelial cell plasticity. Nature Communications, 8(1), 14361. https://doi.org/10.1038/ncomms14361

 

Doheny, D., Manore, S. G., Wong, G. L., & Lo, H.-W. (2020). Hedgehog Signaling and Truncated GLI1 in Cancer. Cells, 9(9), 2114. https://doi.org/10.3390/cells9092114

 

Du, X., Li, Y., Xia, Y.-L., Ai, S.-M., Liang, J., Sang, P., Ji, X.-L., & Liu, S.-Q. (2016). Insights into Protein–Ligand Interactions: Mechanisms, Models, and Methods. International Journal of Molecular Sciences, 17(2), 144. https://doi.org/10.3390/ijms17020144

 

Fornari, F., Giovannini, C., Piscaglia, F., & Gramantieri, L. (2021). Elucidating the Molecular Basis of Sorafenib Resistance in HCC: Current Findings and Future Directions. Journal of Hepatocellular Carcinoma, Volume 8, 741–757. https://doi.org/10.2147/JHC.S285726

 

Fröhlich, E., & Salar-Behzadi, S. (2014). Toxicological Assessment of Inhaled Nanoparticles: Role of in Vivo, ex Vivo, in Vitro, and in Silico Studies. International Journal of Molecular Sciences, 15(3), 4795–4822. https://doi.org/10.3390/ijms15034795

 

Gacche, R. N., & Assaraf, Y. G. (2018). Redundant angiogenic signaling and tumor drug resistance. Drug Resistance Updates, 36, 47–76. https://doi.org/10.1016/j.drup.2018.01.002

 

Garg, P., Malhotra, J., Kulkarni, P., Horne, D., Salgia, R., & Singhal, S. S. (2024). Emerging Therapeutic Strategies to Overcome Drug Resistance in Cancer Cells. Cancers, 16(13), 2478. https://doi.org/10.3390/cancers16132478

 

Islam, T. M. T., Mahat, N. C., Shaker, I. A., Rahman, S. A., Kabir, Md. H., Shohel, M. A., Kamruzzaman, Md., & Tang, A. K. (2024). Investigation of the Relationship Between Brown HT Dye Exposure and Mammary Tumor Development in Female Rats: An Assessment of the Potential Risk of Breast Cancer. Cureus. https://doi.org/10.7759/cureus.73351

 

Itatani, Y., Kawada, K., Yamamoto, T., & Sakai, Y. (2018). Resistance to Anti-Angiogenic Therapy in Cancer—Alterations to Anti-VEGF Pathway. International Journal of Molecular Sciences, 19(4), 1232. https://doi.org/10.3390/ijms19041232

 

Kawiak, A., & Kostecka, A. (2022). Regulation of Bcl-2 Family Proteins in Estrogen Receptor-Positive Breast Cancer and Their Implications in Endocrine Therapy. Cancers, 14(2), 279. https://doi.org/10.3390/cancers14020279

 

Ladd, A. D., Duarte, S., Sahin, I., & Zarrinpar, A. (2024). Mechanisms of drug resistance in HCC. Hepatology, 79(4), 926–940. https://doi.org/10.1097/HEP.0000000000000237

 

MA Bakar. (2018). Advancing Medical Science through Nanobiotechnology: Prospects, Applications, and Future Directions. Journal of Primeasia, 1(1), 1–10. https://doi.org/10.25163/primeasia.1110163

 

Marin, J. J. G., Macias, R. I. R., Monte, M. J., Romero, M. R., Asensio, M., Sanchez-Martin, A., Cives-Losada, C., Temprano, A. G., Espinosa-Escudero, R., Reviejo, M., Bohorquez, L. H., & Briz, O. (2020). Molecular Bases of Drug Resistance in Hepatocellular Carcinoma. Cancers, 12(6), 1663. https://doi.org/10.3390/cancers12061663

 

Mary, Y. S., Mary, Y. S., Rad, A. S., Yadav, R., Celik, I., & Sarala, S. (2021). Theoretical investigation on the reactive and interaction properties of sorafenib – DFT, AIM, spectroscopic and Hirshfeld analysis, docking and dynamics simulation. Journal of Molecular Liquids, 330, 115652. https://doi.org/10.1016/j.molliq.2021.115652

 

MM Hasan. (2019). Advancing Personalized Treatment for Hepatocellular Carcinoma: Integrating Targeted Therapies, Precision Medicine, and Bioengineering for Improved Outcomes. Journal of Primeasia, 1.2(1), 1–14. https://doi.org/10.25163/primeasia.1110015

 

Modi, S. J., & Kulkarni, V. M. (2022). Exploration of structural requirements for the inhibition of VEGFR-2 tyrosine kinase: Binding site analysis of type II, ‘DFG-out’ inhibitors. Journal of Biomolecular Structure and Dynamics, 40(12), 5712–5727. https://doi.org/10.1080/07391102.2021.1872417

 

MSS Khan. (2024). Innovations in Cancer Research and Treatment. Australian Herbal Insight, 7(1), 1–12. https://doi.org/10.25163/ahi.7120050

 

Niazi, S. K., & Mariam, Z. (2023). Computer-Aided Drug Design and Drug Discovery: A Prospective Analysis. Pharmaceuticals, 17(1), 22. https://doi.org/10.3390/ph17010022

 

Rahman, S. S., Klamrak, A., Mahat, N. C., Rahat, R. H., Nopkuesuk, N., Kamruzzaman, M., Janpan, P., Saengkun, Y., Nabnueangsap, J., Soonkum, T., Sangkudruea, P., Jangpromma, N., Kulchat, S., Patramanon, R., Chaveerach, A., Daduang, J., & Daduang, S. (2025). Thyroid Stimulatory Activity of Houttuynia cordata Thunb. Ethanolic Extract in 6-Propyl-Thiouracil-Induced Hypothyroid and STZ Induced Diabetes Rats: In Vivo and In Silico Studies. Nutrients, 17(3), 594. https://doi.org/10.3390/nu17030594

 

Roche, D., Brackenridge, D., & McGuffin, L. (2015). Proteins and Their Interacting Partners: An Introduction to Protein–Ligand Binding Site Prediction Methods. International Journal of Molecular Sciences, 16(12), 29829–29842. https://doi.org/10.3390/ijms161226202

 

Roskoski, R. (2014). The ErbB/HER family of protein-tyrosine kinases and cancer. Pharmacological Research, 79, 34–74. https://doi.org/10.1016/j.phrs.2013.11.002

 

Shah, M., Patel, M., Shah, M., Patel, M., & Prajapati, M. (2024). Computational transformation in drug discovery: A comprehensive study on molecular docking and quantitative structure activity relationship (QSAR). Intelligent Pharmacy, 2(5), 589–595. https://doi.org/10.1016/j.ipha.2024.03.001

 

Tolou-Ghamari, Z. (2024). Review of Hepatocellular Carcinoma and Liver Disease Prevalence. New Emirates Medical Journal, 05. https://doi.org/10.2174/0102506882271605231211102803

 

Tuffery, P., & Derreumaux, P. (2012). Flexibility and binding affinity in protein–ligand, protein–protein and multi-component protein interactions: limitations of current computational approaches. Journal of The Royal Society Interface, 9(66), 20–33. https://doi.org/10.1098/rsif.2011.0584

 

Varanasi, S. K., Chen, D., Liu, Y., Johnson, M. A., Miller, C. M., Ganguly, S., Lande, K., LaPorta, M. A., Hoffmann, F. A., Mann, T. H., Teneche, M. G., Casillas, E., Mangalhara, K. C., Mathew, V., Sun, M., Jensen, I. J., Farsakoglu, Y., Chen, T., Parisi, B., … Kaech, S. M. (2025). Bile acid synthesis impedes tumor-specific T cell responses during liver cancer. Science, 387(6730), 192–201. https://doi.org/10.1126/science.adl4100

 

Zhang, N., Tian, X., Liu, F., Jin, X., Zhang, J., Hao, L., Jiang, S., & Liu, Q. (2025). Reversal of sorafenib resistance in hepatocellular carcinoma by curcumol: insights from network pharmacology, molecular docking, and experimental validation. Frontiers in Pharmacology, 16. https://doi.org/10.3389/fphar.2025.1514997

 

Zhu, A. X. (2008). Development of sorafenib and other molecularly targeted agents in hepatocellular carcinoma. Cancer, 112(2), 250–259. https://doi.org/10.1002/cncr.23175


View Dimensions


View Plumx


View Altmetric



0
Save
0
Citation
34
View
0
Share

Stay connected