Exploration of the Antitumor Mechanism of Fruquintinib in Colorectal Cancer via Autophagy Regulation
Keywords:
fruquintinib, colorectal cancer, cell autophagy, antitumor mechanism
Abstract
Colorectal cancer (CRC) ranks as the second leading cause of cancer-related mortality worldwide, with treatment challenges largely attributed to late-stage diagnoses, frequent recurrences, and resistance to therapy. In recent years, Fruquintinib, a selective vascular endothelial growth factor receptor (VEGFR) inhibitor, has shown notable effectiveness in advanced CRC by targeting angiogenesis. However, CRC cells often activate autophagy in response to hypoxia and nutrient deprivation caused by anti-angiogenic therapy, which diminishes the therapeutic efficacy of Fruquintinib. Autophagy plays a dual role in CRC by suppressing tumorigenesis through the removal of damaged organelles, while facilitating tumor progression and therapeutic resistance through metabolic adaptation in advanced stages. This complexity underscores the therapeutic promise of strategies targeting autophagy. Current studies reveal that Fruquintinib induces autophagy by inhibiting VEGFR signaling, activating AMPK, and suppressing mTOR, while interacting synergistically with other cell death mechanisms such as apoptosis, ferroptosis, and pyroptosis to enhance its antitumor activity. However, excessive autophagy activation may enable tumor cell survival and promote resistance, highlighting the necessity of precise modulation of autophagy in combination therapies. Moreover, preclinical studies indicate that combining Fruquintinib with autophagy modulators significantly enhances its antitumor effects and delays resistance emergence. This review offers a systematic analysis of Fruquintinib's antitumor mechanisms via autophagy modulation and its potential clinical implications. Based on the reviewed evidence, we propose strategies to optimize Fruquintinib-based combination therapies, including the use of autophagy-related biomarkers, autophagy modulators, and precision medicine approaches tailored to tumor genomic profiles, aiming to enhance treatment outcomes for CRC patients.
References
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[8] Sun, Y., Wang, X., Yang, X., et al. (2023). V-ATPase recruitment to ER exit sites switches COPII-mediated transport to lysosomal degradation. Developmental Cell, 58(23), 2761-2775.e5. https://doi.org/10.1016/j.devcel.2023.10.007
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[10] Cao, Z., Tian, K., Ran, Y., et al. (2024). Beclin-1: a therapeutic target at the intersection of autophagy, immunotherapy, and cancer treatment. Frontiers in Immunology, 15, 1506426. https://doi.org/10.3389/fimmu.2024.1506426
[11] Li, X., He, S., Ma, B. (2020). Autophagy and autophagy-related proteins in cancer. Molecular Cancer, 19(1), 12. https://doi.org/10.1186/s12943-020-1138-4
[12] Pan, Y., Zhao, Z., Li, J., et al. (2022). Nuclear Beclin 1 Destabilizes Retinoblastoma Protein to Promote Cell Cycle Progression and Colorectal Cancer Growth. Cancers, 14(19), 4735. https://doi.org/10.3390/cancers14194735
[13] Peng, J. Q., Han, S. M., Chen, Z. H., et al. (2020). Chaperone-mediated autophagy regulates apoptosis and the proliferation of colon carcinoma cells. Biochemical and Biophysical Research Communications, 522(2), 348-354. https://doi.org/10.1016/j.bbrc.2019.11.081
[14] Mukhopadhyay, S., Mahapatra, K. K., Praharaj, P. P., et al. (2022). Recent progress of autophagy signaling in tumor microenvironment and its targeting for possible cancer therapeutics. Seminars in Cancer Biology, 85, 196-208. https://doi.org/10.1016/j.semcancer.2021.09.003
[15] Zhao, Y., Wu, H., Xing, X., et al. (2020). CD13 Induces Autophagy to Promote Hepatocellular Carcinoma Cell Chemoresistance Through the P38/Hsp27/CREB/ATG7 Pathway. Journal of Pharmacology and Experimental Therapeutics, 374(3), 512-520. https://doi.org/10.1124/jpet.120.265637
[16] Chen, Y. F., Yu, Z. L., Lv, M. Y., et al. (2021). Genome-Wide Analysis Reveals Hypoxic Microenvironment Is Associated With Immunosuppression in Poor Survival of Stage II/III Colorectal Cancer Patients. Frontiers in Medicine, 8, 686885. https://doi.org/10.3389/fmed.2021.686885
[17] Zamame Ramirez, J. A., Romagnoli, G. G., Kaneno, R. (2021). Inhibiting autophagy to prevent drug resistance and improve anti-tumor therapy. Life Sciences, 265, 118745. https://doi.org/10.1016/j.lfs.2020.118745
[18] Lee, S. H., Golinska, M., Griffiths, J. R. (2021). HIF-1-Independent Mechanisms Regulating Metabolic Adaptation in Hypoxic Cancer Cells. Cells, 10(9), 2371. https://doi.org/10.3390/cells10092371
[19] Chandra, A., Rick, J., Yagnik, G., et al. (2020). Autophagy as a mechanism for anti-angiogenic therapy resistance. Seminars in Cancer Biology, 66, 75-88. https://doi.org/10.1016/j.semcancer.2019.08.031
[20] Jovanović, L., Nikolić, A., Dragičević, S., et al. (2022). Prognostic relevance of autophagy-related markers p62, LC3, and Beclin1 in ovarian cancer. Croatian Medical Journal, 63(5), 453-460. https://doi.org/10.3325/cmj.2022.63.453
[21] Dasari, A., Sobrero, A., Yao, J., et al. (2021). FRESCO-2: a global Phase III study investigating the efficacy and safety of fruquintinib in metastatic colorectal cancer. Future Oncology, 17(24), 3151-3162. https://doi.org/10.2217/fon-2021-0202
[22] Zhang, W., Zhang, Z., Lou, S., et al. (2022). Efficacy, safety and predictors of combined fruquintinib with programmed death-1 inhibitors for advanced microsatellite-stable colorectal cancer: A retrospective study. Frontiers in Oncology, 12, 929342. https://doi.org/10.3389/fonc.2022.929342
[23] Ding, X., Liu, Y., Zhang, Y., et al. (2023). Efficacy and safety of fruquintinib as third- or further-line therapy for patients with advanced bone and soft tissue sarcoma: a multicenter retrospective study. Anti-Cancer Drugs, 34(7), 877-882. https://doi.org/10.1097/CAD.0000000000001482
[24] Rahman, M. A., Saikat, A. S. M., Rahman, M. S., et al. (2023). Recent Update and Drug Target in Molecular and Pharmacological Insights into Autophagy Modulation in Cancer Treatment and Future Progress. Cells, 12(3), 458. https://doi.org/10.3390/cells12030458
[25] Keyvani-Ghamsari, S., Khorsandi, K., Rasul, A., et al. (2021). Current understanding of epigenetics mechanism as a novel target in reducing cancer stem cells resistance. Clinical Epigenetics, 13(1), 120. https://doi.org/10.1186/s13148-021-01107-4
[26] Bisht, S., Nigam, M., Kunjwal, S. S., et al. (2022). Cancer Stem Cells: From an Insight into the Basics to Recent Advances and Therapeutic Targeting. Stem Cells International, 2022, 1-28. https://doi.org/10.1155/2022/9653244
[27] Verma, A. K., Bharti, P. S., Rafat, S., et al. (2021). Autophagy Paradox of Cancer: Role, Regulation, and Duality. Oxidative Medicine and Cellular Longevity, 2021(1), 8832541. https://doi.org/10.1155/2021/8832541
[28] Neill, T., Chen, C. G., Buraschi, S., et al. (2020). Catabolic degradation of endothelial VEGFA via autophagy. Journal of Biological Chemistry, 295(18), 6064-6079. https://doi.org/10.1074/jbc.RA120.012593
[29] Saikia, R., Joseph, J. (2021). AMPK: a key regulator of energy stress and calcium-induced autophagy. Journal of Molecular Medicine, 99(11), 1539-1551. https://doi.org/10.1007/s00109-021-02125-8
[30] Zhang, Y., Zou, J. Y., Wang, Z., et al. (2019). Fruquintinib: a novel antivascular endothelial growth factor receptor tyrosine kinase inhibitor for the treatment of metastatic colorectal cancer. Cancer Management and Research, 11, 7787-7803. https://doi.org/10.2147/CMAR.S215533
[31] Hsueh, T. C., Chen, P. H., Hong, J. R. (2024). ISKNV Triggers AMPK/mTOR-Mediated Autophagy Signaling through Oxidative Stress, Inducing Antioxidant Enzyme Expression and Enhancing Viral Replication in GF-1 Cells. Viruses, 16(6), 914. https://doi.org/10.3390/v16060914
[32] Zhao, R., Liu, Y., Wang, Z., et al. (2023). UBE2C-mediated Autophagy Inhibition via Ubiquitination of SIRT1 Contributes to Endometrial Cancer Progression. Molecular Cancer Research, 21(6), 564-577. https://doi.org/10.1158/1541-7786.MCR-22-0825
[33] Poillet-Perez, L., Sarry, J. E., Joffre, C. (2021). Autophagy is a major metabolic regulator involved in cancer therapy resistance. Cell Reports, 36(7), 109528. https://doi.org/10.1016/j.celrep.2021.109528
[34] Li, Q., Cheng, X., Zhou, C., et al. (2022). Fruquintinib Enhances the Antitumor Immune Responses of Anti-Programmed Death Receptor-1 in Colorectal Cancer. Frontiers in Oncology, 12, 841977. https://doi.org/10.3389/fonc.2022.841977
[35] Yang, Y., Wang, Q., Song, D., et al. (2020). Lysosomal dysfunction and autophagy blockade contribute to autophagy-related cancer suppressing peptide-induced cytotoxic death of cervical cancer cells through the AMPK/mTOR pathway. Journal of Experimental & Clinical Cancer Research, 39(1), 197. https://doi.org/10.1186/s13046-020-01701-z
[36] Shang, C., Zhu, Y. L., Li, Y. Q., et al. (2021). Autophagy promotes oncolysis of an adenovirus expressing apoptin in human bladder cancer models. Investigational New Drugs, 39(4), 949-960. https://doi.org/10.1007/s10637-021-01073-x
[37] Dong, Y., Zhu, G., Wang, S. F., et al. (2022). Toosendanin, a novel potent vacuolar-type H+-translocating ATPase inhibitor, sensitizes cancer cells to chemotherapy by blocking protective autophagy. International Journal of Biological Sciences, 18(7), 2684-2702. https://doi.org/10.7150/ijbs.71041
[38] Li, J., Guo, W., Bai, Y., et al. (2020). Safety Profile and Adverse Events of Special Interest for Fruquintinib in Chinese Patients with Previously Treated Metastatic Colorectal Cancer: Analysis of the Phase 3 FRESCO Trial. Advances in Therapy, 37(11), 4585-4598. https://doi.org/10.1007/s12325-020-01477-w
[39] Wei, T., Cheng, J., Ji, Y., et al. (2024). Baculovirus-mediated endostatin and angiostatin activation of autophagy through the AMPK/AKT/mTOR pathway inhibits angiogenesis in hepatocellular carcinoma. Open Life Sciences, 19(1), 20220914. https://doi.org/10.1515/biol-2022-0914
[40] Chen, R. J., Lyu, Y. J., Chen, Y. Y., et al. (2021). Chloroquine Potentiates the Anticancer Effect of Pterostilbene on Pancreatic Cancer by Inhibiting Autophagy and Downregulating the RAGE/STAT3 Pathway. Molecules, 26(21), 6741. https://doi.org/10.3390/molecules26216741
[41] Liu, Y., Dai, X., Jiang, S., et al. (2022). Targeted Co-Delivery of Gefitinib and Rapamycin by Aptamer-Modified Nanoparticles Overcomes EGFR-TKI Resistance in NSCLC via Promoting Autophagy. International Journal of Molecular Sciences, 23(14), 8025. https://doi.org/10.3390/ijms23148025
[42] Tan, W. X., Xu, T. M., Zhou, Z. L., et al. (2019). TRP14 promotes resistance to cisplatin by inducing autophagy in ovarian cancer. Oncology Reports, 42(4), 1343-1354. https://doi.org/10.3892/or.2019.7258
[43] Liu, L. Q., Wang, S. B., Shao, Y. F., et al. (2019). Hydroxychloroquine potentiates the anti-cancer effect of bevacizumab on glioblastoma via the inhibition of autophagy. Biomedicine & Pharmacotherapy, 118, 109339. https://doi.org/10.1016/j.biopha.2019.109339
[44] Yao, J., Ma, C., Feng, K., et al. (2022). Focusing on the Role of Natural Products in Overcoming Cancer Drug Resistance: An Autophagy-Based Perspective. Biomolecules, 12(11), 1565. https://doi.org/10.3390/biom12111565
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