天然产物克服非小细胞肺癌EGFR-TKIs耐药的研究进展
Research Progress on Natural Products Overcoming EGFR-TKIs Resistance in Non-Small Cell Lung Cancer
摘要: 非小细胞肺癌(Non-Small Cell Lung Cancer, NSCLC)是肺癌最主要的病理类型，并且常常携带表皮生长因子受体(Epidermal Growth Factor Receptor, EGFR)突变，因此，EGFR酪氨酸激酶抑制剂(EGFR-Tyrosine Kinase Inhibitor, EGFR-TKIs)被广泛应用于临床，并且取得了显著的疗效。然而，随着治疗的进行，获得性耐药性逐渐显现。近年来，天然产物在增强EGFR-TKIs疗效和逆转获得性耐药方面的研究逐渐增多，成为攻克这类难题的潜在方向。
Abstract: Non-small cell lung cancer (NSCLC) is the most predominant pathological type of lung cancer and frequently harbors epidermal growth factor receptor (EGFR) mutations. As a result, EGFR tyrosine kinase inhibitors (EGFR-TKIs) have been widely used in clinical practice, demonstrating significant therapeutic efficacy. However, acquired resistance gradually emerges with prolonged treatment. In recent years, natural products have gained increasing attention for their potential to enhance the efficacy of EGFR-TKIs and reverse acquired resistance, offering a promising strategy to overcome this challenge.
文章引用：宋起凤, 蒋树龙. 天然产物克服非小细胞肺癌EGFR-TKIs耐药的研究进展[J]. 临床个性化医学, 2025, 4(6): 65-71. https://doi.org/10.12677/jcpm.2025.46478

参考文献

[1] Bray, F., Laversanne, M., Sung, H., Ferlay, J., Siegel, R.L., Soerjomataram, I., et al. (2024) Global Cancer Statistics 2022: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: A Cancer Journal for Clinicians, 74, 229-263. [Google Scholar] [CrossRef] [PubMed]
[2] Makarem, M. and Jänne, P.A. (2024) Top Advances of the Year: Targeted Therapy for Lung Cancer. Cancer, 130, 3239-3250. [Google Scholar] [CrossRef] [PubMed]
[3] Kim, J., Park, S., Ku, B.M. and Ahn, M. (2025) Updates on the Treatment of Epidermal Growth Factor Receptor‐Mutant Non-Small Cell Lung Cancer. Cancer, 131, e35778. [Google Scholar] [CrossRef] [PubMed]
[4] Tan, C., Kumarakulasinghe, N.B., Huang, Y., Ang, Y.L.E., Choo, J.R., Goh, B., et al. (2018) Third Generation EGFR TKIs: Current Data and Future Directions. Molecular Cancer, 17, Article No. 29. [Google Scholar] [CrossRef] [PubMed]
[5] Lee, K., Kim, D., Yoon, S., Lee, D.H. and Kim, S. (2021) Exploring the Resistance Mechanisms of Second-Line Osimertinib and Their Prognostic Implications Using Next-Generation Sequencing in Patients with Non-Small-Cell Lung Cancer. European Journal of Cancer, 148, 202-210. [Google Scholar] [CrossRef] [PubMed]
[6] Papadimitrakopoulou, V.A., Wu, Y., Han, J., Ahn, M., Ramalingam, S.S., John, T., et al. (2018) Analysis of Resistance Mechanisms to Osimertinib in Patients with EGFR T790M Advanced NSCLC from the AURA3 Study. Annals of Oncology, 29, viii741. [Google Scholar] [CrossRef] 
[7] Ramalingam, S.S., Cheng, Y., Zhou, C., Ohe, Y., Imamura, F., Cho, B.C., et al. (2018) Mechanisms of Acquired Resistance to First-Line Osimertinib: Preliminary Data from the Phase III FLAURA Study. Annals of Oncology, 29, viii740. [Google Scholar] [CrossRef] 
[8] Hellman, A., Zlotorynski, E., Scherer, S.W., Cheung, J., Vincent, J.B., Smith, D.I., et al. (2002) A Role for Common Fragile Site Induction in Amplification of Human Oncogenes. Cancer Cell, 1, 89-97. [Google Scholar] [CrossRef] [PubMed]
[9] Coleman, N., Hong, L., Zhang, J., Heymach, J., Hong, D. and Le, X. (2021) Beyond Epidermal Growth Factor Receptor: MET Amplification as a General Resistance Driver to Targeted Therapy in Oncogene-Driven Non-Small-Cell Lung Cancer. ESMO Open, 6, Article ID: 100319. [Google Scholar] [CrossRef] [PubMed]
[10] Choudhury, N.J., Marra, A., Sui, J.S.Y., Flynn, J., Yang, S., Falcon, C.J., et al. (2023) Molecular Biomarkers of Disease Outcomes and Mechanisms of Acquired Resistance to First-Line Osimertinib in Advanced EGFR-Mutant Lung Cancers. Journal of Thoracic Oncology, 18, 463-475. [Google Scholar] [CrossRef] [PubMed]
[11] Fuchs, V., Roisman, L., Kian, W., Daniel, L., Dudnik, J., Nechushtan, H., et al. (2021) The Impact of Osimertinib’ Line on Clonal Evolution in EGFRm NSCLC through NGS-Based Liquid Biopsy and Overcoming Strategies for Resistance. Lung Cancer, 153, 126-133. [Google Scholar] [CrossRef] [PubMed]
[12] Wang, H., Du, X., Liu, W., Zhang, C., Li, Y., Hou, J., et al. (2024) Combination of Betulinic Acid and EGFR-TKIs Exerts Synergistic Anti-Tumor Effects against Wild-Type EGFR NSCLC by Inducing Autophagy-Related Cell Death via EGFR Signaling Pathway. Respiratory Research, 25, Article No. 215. [Google Scholar] [CrossRef] [PubMed]
[13] Park, H., Min, T., Chi, G., Choi, Y. and Park, S. (2018) Induction of Apoptosis by Morusin in Human Non-Small Cell Lung Cancer Cells by Suppression of EGFR/STAT3 Activation. Biochemical and Biophysical Research Communications, 505, 194-200. [Google Scholar] [CrossRef] [PubMed]
[14] Ge, Z., Xu, M., Ge, Y., Huang, G., Chen, D., Ye, X., et al. (2023) Inhibiting G6PD by Quercetin Promotes Degradation of EGFR T790M Mutation. Cell Reports, 42, Article ID: 113417. [Google Scholar] [CrossRef] [PubMed]
[15] Liu, P., Xiang, Y., Liu, X., Zhang, T., Yang, R., Chen, S., et al. (2019) Cucurbitacin B Induces the Lysosomal Degradation of EGFR and Suppresses the CIP2A/PP2A/AKT Signaling Axis in Gefitinib-Resistant Non-Small Cell Lung Cancer. Molecules, 24, Article 647. [Google Scholar] [CrossRef] [PubMed]
[16] Chen, P., Huang, H., Wang, Y., Jin, J., Long, W., Chen, K., et al. (2019) Curcumin Overcome Primary Gefitinib Resistance in Non-Small-Cell Lung Cancer Cells through Inducing Autophagy-Related Cell Death. Journal of Experimental & Clinical Cancer Research, 38, Article No. 254. [Google Scholar] [CrossRef] [PubMed]
[17] Huang, G.D., Liu, X.N., Jiang, T., et al. (2023) Luteolin Overcomes Acquired Resistance to Osimertinib in Non-Small Cell Lung Cancer Cells by Targeting the HGF-MET-AKT Pathway. American Journal of Cancer Research, 13, 4145-4162.
[18] Kim, H.S., Oh, H., Kwak, A., Kim, E., Lee, M., Seo, J., et al. (2021) Deoxypodophyllotoxin Inhibits Cell Growth and Induces Apoptosis by Blocking EGFR and MET in Gefitinib-Resistant Non-Small Cell Lung Cancer. Journal of Microbiology and Biotechnology, 31, 559-569. [Google Scholar] [CrossRef] [PubMed]
[19] Yu, J., Zhang, L., Peng, J., Ward, R., Hao, P., Wang, J., et al. (2022) Dictamnine, a Novel C-Met Inhibitor, Suppresses the Proliferation of Lung Cancer Cells by Downregulating the PI3K/AKT/mTOR and MAPK Signaling Pathways. Biochemical Pharmacology, 195, Article ID: 114864. [Google Scholar] [CrossRef] [PubMed]
[20] Chen, Z., Vallega, K.A., Chen, H., Zhou, J., Ramalingam, S.S. and Sun, S. (2022) The Natural Product Berberine Synergizes with Osimertinib Preferentially against Met-Amplified Osimertinib-Resistant Lung Cancer via Direct MET Inhibition. Pharmacological Research, 175, Article ID: 105998. [Google Scholar] [CrossRef] [PubMed]
[21] Tian, X., Gu, T., Lee, M. and Dong, Z. (2022) Challenge and Countermeasures for EGFR Targeted Therapy in Non-Small Cell Lung Cancer. Biochimica et Biophysica Acta (BBA)—Reviews on Cancer, 1877, Article ID: 188645. [Google Scholar] [CrossRef] [PubMed]
[22] Zhu, X., Jiang, H., Li, J., Xu, J. and Fei, Z. (2016) Anticancer Effects of Paris Saponins by Apoptosis and PI3K/AKT Pathway in Gefitinib-Resistant Non-Small Cell Lung Cancer. Medical Science Monitor, 22, 1435-1441. [Google Scholar] [CrossRef] [PubMed]
[23] Liu, J., Zhong, T., Yi, P., Fan, C., Zhang, Z., Liang, G., et al. (2020) A New Epigallocatechin Gallate Derivative Isolated from Anhua Dark Tea Sensitizes the Chemosensitivity of Gefitinib via the Suppression of PI3K/mTOR and Epithelial-Mesenchymal Transition. Fitoterapia, 143, Article ID: 104590. [Google Scholar] [CrossRef] [PubMed]
[24] Chen, T., Zhang, P., Cong, X., Wang, Y., Li, S., Wang, H., et al. (2024) Synergistic Antitumor Activity of Baicalein Combined with Almonertinib in Almonertinib-Resistant Non-Small Cell Lung Cancer Cells through the Reactive Oxygen Species-Mediated PI3K/AKT Pathway. Frontiers in Pharmacology, 15, Article 1405521. [Google Scholar] [CrossRef] [PubMed]
[25] Chen, S., Zhang, Z. and Zhang, J. (2017) Matrine Increases the Inhibitory Effects of Afatinib on H1975 Cells via the IL-6/JAK1/STAT3 Signaling Pathway. Molecular Medicine Reports, 16, 2733-2739. [Google Scholar] [CrossRef] [PubMed]
[26] Wu, Z., Xu, B., Yu, Z., He, Q., Hu, Z., Zhou, S., et al. (2020) Trifolium Flavonoids Overcome Gefitinib Resistance of Non‐Small‐Cell Lung Cancer Cell by Suppressing ERK and STAT3 Signaling Pathways. BioMed Research International, 2020, Article ID: 2491304. [Google Scholar] [CrossRef] [PubMed]
[27] Phan, A.N.H., Hua, T.N.M., Kim, M., Vo, V.T.A., Choi, J., Kim, H., et al. (2016) Gallic Acid Inhibition of Src-Stat3 Signaling Overcomes Acquired Resistance to EGF Receptor Tyrosine Kinase Inhibitors in Advanced Non-Small Cell Lung Cancer. Oncotarget, 7, 54702-54713. [Google Scholar] [CrossRef] [PubMed]
[28] Tang, J., Ren, Y., Zhao, J., Long, F., Chen, J. and Jiang, Z. (2018) Shikonin Enhances Sensitization of Gefitinib against Wild-Type EGFR Non-Small Cell Lung Cancer via Inhibition PKM2/stat3/cyclinD1 Signal Pathway. Life Sciences, 204, 71-77. [Google Scholar] [CrossRef] [PubMed]
[29] Tang, J., Long, F., Zhao, J., Hang, J., Ren, Y., Chen, J., et al. (2019) The Effects and Mechanisms by Which Saikosaponin-D Enhances the Sensitivity of Human Non-Small Cell Lung Cancer Cells to Gefitinib. Journal of Cancer, 10, 6666-6672. [Google Scholar] [CrossRef] [PubMed]
[30] Min, T., Park, H., Ha, K., Chi, G., Choi, Y. and Park, S. (2019) Suppression of EGFR/STAT3 Activity by Lupeol Contributes to the Induction of the Apoptosis of Human Non-Small Cell Lung Cancer Cells. International Journal of Oncology, 55, 320-330. [Google Scholar] [CrossRef] [PubMed]
[31] Tian, X., Wang, R., Gu, T., Ma, F., Laster, K.V., Li, X., et al. (2022) Costunolide Is a Dual Inhibitor of MEK1 and AKT1/2 That Overcomes Osimertinib Resistance in Lung Cancer. Molecular Cancer, 21, Article No. 193. [Google Scholar] [CrossRef] [PubMed]
[32] Fan, Q., Liang, X., Xu, Z., Li, S., Han, S., Xiao, Y., et al. (2023) Pedunculoside Inhibits Epithelial-Mesenchymal Transition and Overcomes Gefitinib-Resistant Non-Small Cell Lung Cancer through Regulating MAPK and Nrf2 Pathways. Phytomedicine, 116, Article ID: 154884. [Google Scholar] [CrossRef] [PubMed]
[33] Zhou, Y., Huang, S., Guo, Y., Ran, M., Shan, W., Chen, W., et al. (2023) Epigallocatechin Gallate Circumvents Drug‐induced Resistance in Non‐Small‐Cell Lung Cancer by Modulating Glucose Metabolism and AMPK/AKT/MAPK Axis. Phytotherapy Research, 37, 5837-5853. [Google Scholar] [CrossRef] [PubMed]
[34] Lu, M., Liu, B., Xiong, H., Wu, F., Hu, C. and Liu, P. (2019) Trans‐3, 5, 4’‐Trimethoxystilbene Reduced Gefitinib Resistance in NSCLCs via Suppressing MAPK/AKT/Bcl‐2 Pathway by Upregulation of miR‐345 and miR‐498. Journal of Cellular and Molecular Medicine, 23, 2431-2441. [Google Scholar] [CrossRef] [PubMed]
[35] Yang, Q., Chen, W., Xu, Y., Lv, X., Zhang, M. and Jiang, H. (2018) Polyphyllin I Modulates MALAT1/STAT3 Signaling to Induce Apoptosis in Gefitinib-Resistant Non-Small Cell Lung Cancer. Toxicology and Applied Pharmacology, 356, 1-7. [Google Scholar] [CrossRef] [PubMed]
[36] Li, Y., Wang, Y., Niu, K., Chen, X., Xia, L., Lu, D., et al. (2016) Clinical Benefit from EGFR-TKI plus Ginsenoside Rg3 in Patients with Advanced Non-Small Cell Lung Cancer Harboring EGFR Active Mutation. Oncotarget, 7, 70535-70545. [Google Scholar] [CrossRef] [PubMed]
[37] China Medical University (2017) β-Elemene Combine with EGFR-TKI for Advanced EGFR-TKI-Resistant NSCLC [Clinical Trial Registration].
https://clinicaltrials.gov/ct2/show/NCT03123484