CSCIED

期刊目次

加入编委

期刊订阅

添加您的邮件地址以接收即将发行期刊数据:

Open Access Article

International Journal of Clinical Research. 2022; 6: (2) ; 19-24 ; DOI: 10.12208/j.ijcr.20220048.

Advances on Resistance Mechanisms of Trastuzumab
曲妥珠单抗耐药机制研究进展

作者: 邢一舒, 王赛琪, 吕慧芳, 聂彩云, 王建正, 赵慧晨, 陈小兵 *

郑州大学附属肿瘤医院,河南省肿瘤医院消化内科 河南郑州

*通讯作者: 陈小兵,单位:郑州大学附属肿瘤医院,河南省肿瘤医院消化内科 河南郑州;

发布时间: 2022-04-24 总浏览量: 1521

摘要

曲妥珠单抗是首个靶向人类表皮生长因子受体-2(Human Epidermal Growth Factor Receptor 2,HER2)的人源化单克隆抗体药物,极大地改善了HER2阳性乳腺癌与胃癌患者的治疗效果及预后,成为HER2阳性晚期乳腺癌与胃癌一线治疗策略。然而,多数患者在使用曲妥珠单抗治疗一年后发生继发耐药,导致疾病进展。研究表明,HER2蛋白结构改变、其他人类表皮生长因子受体(Human Epidermal Growth Factor Receptor,HER)家族受体及其配体信号通路激活、下游磷脂酰肌醇-3激酶(phosphoinositide-3-kinase,PI3K)信号通路改变、上皮间质转化(epithelial-mesenchymal transition,EMT)发生以及抗体依赖的细胞介导的细胞毒作用 (antibody-dependent cell-mediated cytotoxicity,ADCC)等多种机制参与了曲妥珠单抗耐药,本文就曲妥珠单抗耐药机制进行综述,为曲妥珠单抗的治疗提供预测生物标志物、克服耐药的方法,进行更加有效的靶向用药或者联合治疗从而改善患者预后。

关键词: 曲妥珠单抗耐药;HER2;PI3K信号通路;EMT;ADCC

Abstract

Trastuzumab, thefirstmonoclonal antibody targeting Human Epidermal Growth Factor Receptor 2 (HER2) hasimprovedthetreatment effect andprognosis of patients with HER2-positive breast cancer and gastric cancer. Trastuzumab has already been the first-line treatment medicine in aforementioned advanced cancers. However, most patients develop acquired resistance after 1 year, resulting in the disease progression. Researches indicate that there are multiple mechanisms mediating trastuzumab resistance such as the change of HER2 protein structure, activation of signaling pathways among other members of HER Family and their ligands, changes of downstream PI3K signaling pathway, epithelial-mesenchymal transition, antibody-dependent cell-mediated cytotoxicity(ADCC) and so on. In this review, we summarize the mechanisms of trastuzumab resistance, in order to provide predictive biomarkers and overcome resistance of trastuzumab therapy. Furthermore, we hope to find more effective targeted drugs or combination therapies.

Key words: Trastuzumab Resistance; HER2; PI3K; EMT; ADCC

参考文献 References

[1] Elster N, Collins D M, Toomey S, et al. HER2-family signalling mechanisms, clinical implications and targeting in breast cancer[J]. Breast Cancer Research and Treatment, 2015, 149(1):5-15.

[2] Zugazagoitia J, Molina-Pinelo S, Lopez-Rios F, et al. Biological therapies in nonsmall cell lung cancer[J]. European Respiratory Journal, 2017, 49(3):1601520.

[3] Yu A F, Yadav N U, Lung B Y, et al. Trastuzumab interruption and treatment-induced cardiotoxicity in early HER2-positive breast cancer[J]. Breast Cancer Research and Treatment,2015,149(2):489-495.

[4] David J, William P, Gregory J R, et al. Clinical definition of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer.[J]. Journal of Clinical Oncology, 2010, 28(2):357-360.

[5] Tinoco G, Warsch S, Glück S, et al. Treating Breast Cancer in the 21st Century: Emerging Biological Therapies[J]. Journal of Cancer,2013,4(2):117-132.

[6] Gagliato D D M, Jardim D L F, Marchesi M S P, et al. Mechanisms of resistance and sensitivity to anti-HER2 therapies in HER2+ breast cancer[J]. Oncotarget, 2016, 7(39).

[7] Hilda W, Roland L, Ava K, et al. Integrating molecular mechanisms and clinical evidence in the management of trastuzumab resistant or refractory HER-2⁺ metastatic breast cancer.[J]. The oncologist,2011,16(11).

[8] Scaltriti M, Rojo F, Ocaa A, et al. Expression of p95HER2, a Truncated Form of the HER2 Receptor, and Response to Anti-HER2 Therapies in Breast Cancer[J]. Journal of the National Cancer Institute, 2007, 99(8):628-638.

[9] Mitra D, Brumlik M J, Okamgba S U,et al. An oncogenic isoform of HER2 associated with locally disseminated breast cancer and trastuzumab resistance[J]. Molecular Cancer Therapeutics, 2009, 8(8):2152.

[10] Zardavas D, Phillips W A, Loi S. PIK3CA mutations in breast cancer: reconciling findings from preclinical and clinical data[J]. Breast cancer research : BCR,2014,16(1):201.

[11] Cizkova M, Susini A, Vacher S, et al. PIK3CA mutation impact on survival in breast cancer patients and in ERalpha, PR and ERBB2-based subgroups[J]. Breast Cancer Res,2012,14(1):R28.

[12] Davis N M, Sokolosky M, Stadelman K, et al. Deregulation of the EGFR/PI3K/PTEN/Akt/mTORC1 pathway in breast cancer: possibilities for therapeutic intervention[J]. Oncotarget,2014,5(13):4603-4650.

[13] Mei‐Ling Chong, Loh M, Thakkar B, et al. Phosphatidylinositol-3-kinase pathway aberrations in gastric and colorectal cancer: Meta-analysis, co-occurrence and ethnic variation[J]. International Journal of Cancer, 2013, 134(5):1232-1238.

[14] Esteva F J, Guo H, Zhang S, et al. PTEN, PIK3CA, p-AKT, and p-p70S6K Status[J]. The American Journal of Pathology,2010,177(4):1647-1656.

[15] Esteva F J. Role of HER3 expression and PTEN loss in patients with HER2-overexpressing metastatic breast cancer (MBC) who received taxane plus trastuzumab treatment[J]. Breast diseases,2014,25(3).

[16] Anastasi S, Sala G, Huiping C, et al. Loss of RALT/MIG-6 expression in ERBB2-amplified breast carcinomas enhances ErbB-2 oncogenic potency and favors resistance to Herceptin[J]. Oncogene, 24(28):4540-8.

[17] Yarden Y, Pines G. Yarden Y, Pines G. The ERBB network: at last, cancer therapy meets systems biology [J]. Nature Reviews Cancer, 2012, 12(8):553-563.

[18] Gallardo A, Lerma E, Escuin D, et al. Increased signalling of EGFR and IGF1R, and deregulation of PTEN/PI3K/Akt pathway are related with trastuzumab resistance in HER2 breast carcinomas[J]. British Journal of Cancer, 2012, 106(8):1367-1373.

[19] José B, Ian B, Holger E, et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial.[J]. Lancet (London, England),2012,379(9816).

[20] Untch M P, Loibl S M, Bischoff J M, et al. Lapatinib versus trastuzumab in combination with neoadjuvant anthracycline-taxane-based chemotherapy (GeparQuinto, GBG 44): a randomised phase 3 trial[J]. The lancet oncology,2012,13(2):135-144.

[21] Ritwik G, Archana N, Shizhen Emily W, et al. Trastuzumab has preferential activity against breast cancers driven by HER2 homodimers.[J]. Cancer research,2011,71(5).

[22] Shizhen Emily W, Bin X, Marta G, et al. Transforming growth factor beta engages TACE and ErbB3 to activate phosphatidylinositol-3 kinase/Akt in ErbB2-overexpressing breast cancer and desensitizes cells to trastuzumab.[J]. Molecular and cellular biology,2008,28(18).

[23] Dianbo Y, Chaoliu D, Songlin P. Mechanism of the mesenchymal-epithelial transition and its relationship with metastatic tumor formation.[J]. Molecular cancer research : MCR,2011,9(12).

[24] Wu Y, Ginther C, Kim J , et al. Expression of Wnt3 Activates Wnt/β-Catenin Pathway and Promotes EMT-like Phenotype in Trastuzumab-Resistant HER2-Overexpressing Breast Cancer Cells[J]. Molecular Cancer Research, 2012, 10(12):1597-1606.

[25] 叶星明,王淋,贾静,等. miR-375靶向YAP1调控上皮-间质转化参与乳腺癌细胞曲妥珠单抗的耐药[J]. 中国癌症杂志,2021,31(1):8.

[26] John M L, Patrick S, Hui L, et al. The Hippo pathway target, YAP, promotes metastasis through its TEAD-interaction domain.[J]. Proceedings of the National Academy of Sciences of the United States of America,2012,109(37).

[27] Clynes R A, Towers T L, Presta L G, et al. Inhibitory Fc receptors modulate in vivo cytotoxicity against tumor targets.[J]. Nature Medicine, 2000, 6(4):443-446.

[28] Michaud H, Eliaou J, Lafont V, et al. Tumor antigen-targeting monoclonal antibody-based immunotherapy: Orchestrating combined strategies for the development of long-term antitumor immunity[J]. Oncoimmunology.,2014,3(9).

[29] Zhu E, Gai S, Opel C, et al. Synergistic Innate and Adaptive Immune Response to Combination Immunotherapy with Anti-Tumor Antigen Antibodies and Extended Serum Half-Life IL-2[J]. Cancer Cell, 2015, 27(4):489-501.

[30] Chao M P, Alizadeh A A, Tang C, et al. Anti-CD47 antibody synergizes with rituximab to promote phagocytosis and eradicate non-Hodgkin lymphoma.[J]. Cell, 2010, 142(5):699-713.

[31] Perruche S, Zhang P, Liu Y, et al. CD3-specific antibody-induced immune tolerance involves transforming growth factor-beta from phagocytes digesting apoptotic T cells.[J]. Nature medicine, 2008, 14(5):528-535.

[32] Su S, Zhao, Y Xing, et al. Immune Checkpoint Inhibition Overcomes ADCP-Induced Immunosuppression by Macrophages[J]. Cell, 2018, 175(2):442-457.e23.

[33] Janjigian Y Y, Maron S B, Chatila W K , et al. First-line pembrolizumab and trastuzumab in HER2-positive oesophageal, gastric, or gastro-oesophageal junction cancer: an open-label, single-arm, phase 2 trial[J]. The Lancet Oncology, 2020, 21(6).

[34] Samantha E G, Katherine J W, Jayashree P J, et al. Mechanisms of Adipocytokine-Mediated Trastuzumab Resistance in HER2-Positive Breast Cancer Cell Lines.[J]. Current pharmacogenomics and personalized medicine,2013,11(1).

[35] Joshi J P, Brown N E, Griner S E, et al. Growth differentiation factor 15 (GDF15)-mediated HER2 phosphorylation reduces trastuzumab sensitivity of HER2-overexpressing breast cancer cells[J]. Biochemical Pharmacology,2011,82(9):1090-1099.


引用本文

邢一舒, 王赛琪, 吕慧芳, 聂彩云, 王建正, 赵慧晨, 陈小兵, 曲妥珠单抗耐药机制研究进展[J]. 国际临床研究杂志, 2022; 6: (2) : 19-24.