Venetoclax治疗急性髓系白血病的耐药机制与克服策略进展
Advances in Resistance Mechanisms and Overcoming Strategies of Venetoclax in Acute Myeloid Leukemia
摘要: 老年或不适合强化化疗的急性髓系白血病(AML)患者，其治疗选择通常有限。BCL-2抑制剂Venetoclax联合去甲基化药物显著提高缓解率并延长生存，但原发无应答与复发仍常见，提示耐药机制复杂且具有动态演化特征。本文围绕BCL-2抑制剂耐药的多维机制进行综述：抗凋亡网络代偿与凋亡阈值升高、促存活信号激活与代谢重编程、骨髓微环境庇护，以及治疗压力下的克隆演化与细胞状态可塑性；进而总结了遗传学、蛋白与功能组学以及微小残留病(MRD)监测/克隆追踪等生物标志物体系在疗效预测与动态监测中的价值；并归纳了基于上述机制的联合治疗策略，如靶向MCL-1/BCL-XL、抑制FLT3/IDH/RAS-MAPK通路、干预代谢与微环境/免疫调控、以及运用表观遗传调节药物等。最后，探讨了该领域面临的关键挑战与未来发展方向，并强调了整合多组学技术与纵向动态监测对于构建“动态个体化治疗”范式的重要性。
Abstract: Treatment options for elderly or unfit patients with acute myeloid leukemia (AML) are often limited. The BCL-2 inhibitor venetoclax combined with hypomethylating agents significantly improves response rates and prolongs survival; however, primary non-response and relapse remain common, indicating complex and dynamically evolving resistance mechanisms. This review focuses on the multidimensional mechanisms underlying resistance to BCL-2 inhibitors, including compensatory upregulation of anti-apoptotic networks and an elevated apoptotic threshold, activation of pro-survival signaling and metabolic reprogramming, protection by the bone marrow microenvironment, as well as clonal evolution and cell state plasticity under therapeutic pressure. Furthermore, we summarize the value of biomarker systems—such as genetic, protein-based and functional omics approaches, along with minimal residual disease (MRD) monitoring and clonal tracking—in predicting response and enabling dynamic surveillance. Combination strategies targeting these mechanisms are also reviewed, including inhibition of MCL-1/BCL-XL, blockade of FLT3/IDH/RAS-MAPK pathways, intervention in metabolism and microenvironment/immune regulation, and the use of epigenetic modulators. Finally, we discuss key challenges and future directions in this field, emphasizing that integrating multi-omics technologies with longitudinal dynamic monitoring is essential for establishing a paradigm of “dynamic individualized therapy”.
文章引用：任桂林, 王利. Venetoclax治疗急性髓系白血病的耐药机制与克服策略进展[J]. 临床医学进展, 2026, 16(5): 3252-3259. https://doi.org/10.12677/acm.2026.1652145

参考文献

[1] Nwosu, G.O., Ross, D.M., Powell, J.A. and Pitson, S.M. (2024) Venetoclax Therapy and Emerging Resistance Mechanisms in Acute Myeloid Leukaemia. Cell Death & Disease, 15, Article No. 413. [Google Scholar] [CrossRef] [PubMed]
[2] Ong, F., Kim, K. and Konopleva, M.Y. (2022) Venetoclax Resistance: Mechanistic Insights and Future Strategies. Cancer Drug Resistance, 5, 380-400. [Google Scholar] [CrossRef] [PubMed]
[3] Wei, A.H., Loo, S. and Daver, N. (2025) How I Treat Patients with AML Using Azacitidine and Venetoclax. Blood, 145, 1237-1250. [Google Scholar] [CrossRef] [PubMed]
[4] DiNardo, C.D., Jonas, B.A., Pullarkat, V., Thirman, M.J., Garcia, J.S., Wei, A.H., et al. (2020) Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia. New England Journal of Medicine, 383, 617-629. [Google Scholar] [CrossRef] [PubMed]
[5] Chatzilygeroudi, T., Karantanos, T. and Pappa, V. (2025) Unraveling Venetoclax Resistance: Navigating the Future of HMA/Venetoclax-Refractory AML in the Molecular Era. Cancers, 17, Article No. 1586. [Google Scholar] [CrossRef] [PubMed]
[6] De Bellis, E., Imbergamo, S., Candoni, A., Liço, A., Tanasi, I., Mauro, E., et al. (2022) Venetoclax in Combination with Hypomethylating Agents in Previously Untreated Patients with Acute Myeloid Leukemia Ineligible for Intensive Treatment: A Real-Life Multicenter Experience. Leukemia Research, 114, Article 106803. [Google Scholar] [CrossRef] [PubMed]
[7] Diamantidis, M.D. (2025) Factors Affecting Response and Resistance to Venetoclax in Acute Myeloid Leukemia. Frontiers in Oncology, 15, Article 1577908. [Google Scholar] [CrossRef] 
[8] Garciaz, S., Hospital, M., Collette, Y. and Vey, N. (2024) Venetoclax Resistance in Acute Myeloid Leukemia. Cancers, 16, Article No. 1091. [Google Scholar] [CrossRef] [PubMed]
[9] Tse, C., Shoemaker, A.R., Adickes, J., Anderson, M.G., Chen, J., Jin, S., et al. (2008) ABT-263: A Potent and Orally Bioavailable BCL-2 Family Inhibitor. Cancer Research, 68, 3421-3428. [Google Scholar] [CrossRef] [PubMed]
[10] Mason, K.D., Carpinelli, M.R., Fletcher, J.I., Collinge, J.E., Hilton, A.A., Ellis, S., et al. (2007) Programmed Anuclear Cell Death Delimits Platelet Life Span. Cell, 128, 1173-1186. [Google Scholar] [CrossRef] [PubMed]
[11] Souers, A.J., Leverson, J.D., Boghaert, E.R., Ackler, S.L., Catron, N.D., Chen, J., et al. (2013) ABT-199, a Potent and Selective BCL-2 Inhibitor, Achieves Antitumor Activity While Sparing Platelets. Nature Medicine, 19, 202-208. [Google Scholar] [CrossRef] [PubMed]
[12] Lu, H., Wang, H., Wang, Q., Huang, D., Han, Y., Wang, H., et al. (2025) Dynamic Evolution of Venetoclax Resistance in Acute Myeloid Leukemia Unveiled by Longitudinal Single-Cell RNA-seq. Cancer Letters, 628, Article 217853. [Google Scholar] [CrossRef] [PubMed]
[13] Pan, R., Hogdal, L.J., Benito, J.M., Bucci, D., Han, L., Borthakur, G., et al. (2014) Selective BCL-2 Inhibition by ABT-199 Causes On-Target Cell Death in Acute Myeloid Leukemia. Cancer Discovery, 4, 362-375. [Google Scholar] [CrossRef] [PubMed]
[14] Tatarata, Q.Z., Wang, Z. and Konopleva, M. (2024) BCL-2 Inhibition in Acute Myeloid Leukemia: Resistance and Combinations. Expert Review of Hematology, 17, 935-946. [Google Scholar] [CrossRef] [PubMed]
[15] Zhang, Q., Riley-Gillis, B., Han, L., Jia, Y., Lodi, A., Zhang, H., et al. (2022) Activation of RAS/MAPK Pathway Confers MCL-1 Mediated Acquired Resistance to BCL-2 Inhibitor Venetoclax in Acute Myeloid Leukemia. Signal Transduction and Targeted Therapy, 7, Article No. 51. [Google Scholar] [CrossRef] [PubMed]
[16] Zhang, H., Nakauchi, Y., Köhnke, T., Stafford, M., Bottomly, D., Thomas, R., et al. (2020) Integrated Analysis of Patient Samples Identifies Biomarkers for Venetoclax Efficacy and Combination Strategies in Acute Myeloid Leukemia. Nature Cancer, 1, 826-839. [Google Scholar] [CrossRef] [PubMed]
[17] Chen, X., Glytsou, C., Zhou, H., Narang, S., Reyna, D.E., Lopez, A., et al. (2019) Targeting Mitochondrial Structure Sensitizes Acute Myeloid Leukemia to Venetoclax Treatment. Cancer Discovery, 9, 890-909. [Google Scholar] [CrossRef] [PubMed]
[18] Kasper, S., Breitenbuecher, F., Heidel, F., Hoffarth, S., Markova, B., Schuler, M., et al. (2012) Targeting MCL-1 Sensitizes FLT3-ITD-Positive Leukemias to Cytotoxic Therapies. Blood Cancer Journal, 2, e60. [Google Scholar] [CrossRef] [PubMed]
[19] Yoshimoto, G., Miyamoto, T., Jabbarzadeh-Tabrizi, S., Iino, T., Rocnik, J.L., Kikushige, Y., et al. (2009) FLT3-ITD Up-Regulates MCL-1 to Promote Survival of Stem Cells in Acute Myeloid Leukemia via FLT3-ITD-Specific STAT5 Activation. Blood, 114, 5034-5043. [Google Scholar] [CrossRef] [PubMed]
[20] Yamatani, K., Ai, T., Saito, K., Suzuki, K., Hori, A., Kinjo, S., et al. (2022) Inhibition of BCL2A1 by STAT5 Inactivation Overcomes Resistance to Targeted Therapies of FLT3-ITD/D835 Mutant AML. Translational Oncology, 18, Article 101354. [Google Scholar] [CrossRef] [PubMed]
[21] Moujalled, D.M., Brown, F.C., Chua, C.C., Dengler, M.A., Pomilio, G., Anstee, N.S., et al. (2023) Acquired Mutations in BAX Confer Resistance to Bh3-Mimetic Therapy in Acute Myeloid Leukemia. Blood, 141, 634-644. [Google Scholar] [CrossRef] [PubMed]
[22] Carter, B.Z., Mak, P.Y., Tao, W., Ayoub, E., Ostermann, L.B., Huang, X., et al. (2023) Combined Inhibition of BCL-2 and MCL-1 Overcomes BAX Deficiency-Mediated Resistance of TP53-Mutant Acute Myeloid Leukemia to Individual BH3 Mimetics. Blood Cancer Journal, 13, Article No. 57. [Google Scholar] [CrossRef] [PubMed]
[23] Blombery, P., Anderson, M.A., Gong, J., Thijssen, R., Birkinshaw, R.W., Thompson, E.R., et al. (2019) Acquisition of the Recurrent Gly101val Mutation in BCL2 Confers Resistance to Venetoclax in Patients with Progressive Chronic Lymphocytic Leukemia. Cancer Discovery, 9, 342-353. [Google Scholar] [CrossRef] [PubMed]
[24] Blombery, P., Thompson, E.R., Nguyen, T., Birkinshaw, R.W., Gong, J., Chen, X., et al. (2020) Multiple BCL2 Mutations Cooccurring with Gly101Val Emerge in Chronic Lymphocytic Leukemia Progression on Venetoclax. Blood, 135, 773-777. [Google Scholar] [CrossRef] [PubMed]
[25] Bisaillon, R., Moison, C., Thiollier, C., Krosl, J., Bordeleau, M., Lehnertz, B., et al. (2019) Genetic Characterization of ABT-199 Sensitivity in Human AML. Leukemia, 34, 63-74. [Google Scholar] [CrossRef] [PubMed]
[26] Lin, S., Schneider, C., Su, A.H., Alexe, G., Root, D.E. and Stegmaier, K. (2024) The UBE2J2/UBE2K-MARCH5 Ubiquitination Machinery Regulates Apoptosis in Response to Venetoclax in Acute Myeloid Leukemia. Leukemia, 38, 652-656. [Google Scholar] [CrossRef] [PubMed]
[27] Nechiporuk, T., Kurtz, S.E., Nikolova, O., Liu, T., Jones, C.L., D'Alessandro, A., et al. (2019) The TP53 Apoptotic Network Is a Primary Mediator of Resistance to BCL2 Inhibition in AML Cells. Cancer Discovery, 9, 910-925. [Google Scholar] [CrossRef] [PubMed]
[28] Aubrey, B.J., Kelly, G.L., Janic, A., Herold, M.J. and Strasser, A. (2018) How Does P53 Induce Apoptosis and How Does This Relate to P53-Mediated Tumour Suppression? Cell Death & Differentiation, 25, 104-113. [Google Scholar] [CrossRef] [PubMed]
[29] Thijssen, R., Diepstraten, S.T., Moujalled, D., Chew, E., Flensburg, C., Shi, M.X., et al. (2021) Intact TP-53 Function Is Essential for Sustaining Durable Responses to BH3-Mimetic Drugs in Leukemias. Blood, 137, 2721-2735. [Google Scholar] [CrossRef] [PubMed]
[30] Lagadinou, E.D., Sach, A., Callahan, K., Rossi, R.M., Neering, S.J., Minhajuddin, M., et al. (2013) BCL-2 Inhibition Targets Oxidative Phosphorylation and Selectively Eradicates Quiescent Human Leukemia Stem Cells. Cell Stem Cell, 12, 329-341. [Google Scholar] [CrossRef] [PubMed]
[31] Pollyea, D.A., Stevens, B.M., Jones, C.L., Winters, A., Pei, S., Minhajuddin, M., et al. (2018) Venetoclax with Azacitidine Disrupts Energy Metabolism and Targets Leukemia Stem Cells in Patients with Acute Myeloid Leukemia. Nature Medicine, 24, 1859-1866. [Google Scholar] [CrossRef] [PubMed]
[32] Sharon, D., Cathelin, S., Mirali, S., Di Trani, J.M., Yanofsky, D.J., Keon, K.A., et al. (2019) Inhibition of Mitochondrial Translation Overcomes Venetoclax Resistance in AML through Activation of the Integrated Stress Response. Science Translational Medicine, 11, eaax2863. [Google Scholar] [CrossRef] [PubMed]
[33] Stevens, B.M., Jones, C.L., Pollyea, D.A., Culp-Hill, R., D’Alessandro, A., Winters, A., et al. (2020) Fatty Acid Metabolism Underlies Venetoclax Resistance in Acute Myeloid Leukemia Stem Cells. Nature Cancer, 1, 1176-1187. [Google Scholar] [CrossRef] [PubMed]
[34] Jones, C.L., Stevens, B.M., Pollyea, D.A., Culp-Hill, R., Reisz, J.A., Nemkov, T., et al. (2020) Nicotinamide Metabolism Mediates Resistance to Venetoclax in Relapsed Acute Myeloid Leukemia Stem Cells. Cell Stem Cell, 27, 748-764.e4. [Google Scholar] [CrossRef] [PubMed]
[35] Yu, X., Munoz-Sagredo, L., Streule, K., Muschong, P., Bayer, E., Walter, R.J., et al. (2021) CD44 Loss of Function Sensitizes AML Cells to the BCL-2 Inhibitor Venetoclax by Decreasing Cxcl12-Driven Survival Cues. Blood, 138, 1067-1080. [Google Scholar] [CrossRef] [PubMed]
[36] Thijssen, R., Slinger, E., Weller, K., Geest, C.R., Beaumont, T., van Oers, M.H.J., et al. (2015) Resistance to ABT-199 Induced by Microenvironmental Signals in Chronic Lymphocytic Leukemia Can Be Counteracted by CD20 Antibodies or Kinase Inhibitors. Haematologica, 100, e302-e306. [Google Scholar] [CrossRef] [PubMed]
[37] Wei, A.H., Roberts, A.W., Spencer, A., Rosenberg, A.S., Siegel, D., Walter, R.B., et al. (2020) Targeting MCL-1 in Hematologic Malignancies: Rationale and Progress. Blood Reviews, 44, Article 100672. [Google Scholar] [CrossRef] [PubMed]
[38] Tron, A.E., Belmonte, M.A., Adam, A., Aquila, B.M., Boise, L.H., Chiarparin, E., et al. (2018) Discovery of Mcl-1-Specific Inhibitor AZD5991 and Preclinical Activity in Multiple Myeloma and Acute Myeloid Leukemia. Nature Communications, 9, Article No. 5341. [Google Scholar] [CrossRef] [PubMed]
[39] Short, N.J., Daver, N., Dinardo, C.D., Kadia, T., Nasr, L.F., Macaron, W., et al. (2024) Azacitidine, Venetoclax, and Gilteritinib in Newly Diagnosed and Relapsed or Refractory FLT3-Mutated AML. Journal of Clinical Oncology, 42, 1499-1508. [Google Scholar] [CrossRef] [PubMed]
[40] Sango, J., Carcamo, S., Sirenko, M., Maiti, A., Mansour, H., Ulukaya, G., et al. (2024) RAS-Mutant Leukaemia Stem Cells Drive Clinical Resistance to Venetoclax. Nature, 636, 241-250. [Google Scholar] [CrossRef] [PubMed]
[41] Chyla, B., Daver, N., Doyle, K., McKeegan, E., Huang, X., Ruvolo, V., et al. (2018) Genetic Biomarkers of Sensitivity and Resistance to Venetoclax Monotherapy in Patients with Relapsed Acute Myeloid Leukemia. American Journal of Hematology, 93, E202-E205. [Google Scholar] [CrossRef] [PubMed]
[42] Waclawiczek, A., Leppä, A., Renders, S., Stumpf, K., Reyneri, C., Betz, B., et al. (2023) Combinatorial BCL2 Family Expression in Acute Myeloid Leukemia Stem Cells Predicts Clinical Response to Azacitidine/Venetoclax. Cancer Discovery, 13, 1408-1427. [Google Scholar] [CrossRef] [PubMed]

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