恶性黑色素瘤靶向治疗及其耐药机制研究进展

刘一帆; 罗星; 宋天慈; 杨志惠

doi:10.12259/j.issn.2095-610X.S20250222

恶性黑色素瘤靶向治疗及其耐药机制研究进展

doi: 10.12259/j.issn.2095-610X.S20250222

刘一帆^{1, 2},
罗星^{2, 3},
宋天慈⁴,
杨志惠^{2, 3, ,}

1.
西南医科大学基础医学院，四川泸州 646000
2.
重大疾病精准病理诊断泸州市重点实验室，四川泸州　646000
3.
西南医科大学附属医院病理科，四川泸州　646000
4.
齐鲁医药学院临床医学院，山东淄博　255300

基金项目: 国家自然科学基金（82273395）

详细信息

作者简介:
刘一帆（1998～），男，山东临沂人，在读硕士研究生，主要从事肿瘤发生发展机制研究工作

通讯作者:
杨志惠，E-mail：yzhih73@swmu.edu.cn

中图分类号: R730.23
计量
- 文章访问数: 476
- HTML全文浏览量: 306
- PDF下载量: 39
- 被引次数: 0
出版历程
- 收稿日期: 2024-07-19
- 网络出版日期: 2025-01-05
- 刊出日期: 2025-02-18

Research Progress on Targeted Therapy and Resistance Mechanisms of Malignant Melanoma

Yifan LIU^{1, 2},
Xing LUO^{2, 3},
Tianci SONG⁴,
Zhihui YANG^{2, 3
, ,}

1.
School of Basic Medical Sciences，Southwest Medical University，Luzhou Sichuan 646000
2.
Key Laboratory for Precision Pathological Diagnosis of Major Diseases，Luzhou Sichuan 646000
3.
Affiliated Hospital of Southwest Medical University，Luzhou Sichuan 646000
4.
School of Clinical Medicine，Qilu Medical University，Zibo Shandong 255300，China

摘要

摘要: 恶性黑色素瘤是一种侵袭性极强的肿瘤，在早期可行外科手术切除治疗。晚期黑色素瘤细胞的侵袭能力和增殖能力不断增强，传统治疗方法如放疗、化疗和免疫治疗等效果有限，患者预后差。由于恶性黑色素瘤发病存在多条分子通路的突变，因而靶向治疗成为晚期恶性黑色素瘤患者较为可行的治疗方法，多数患者可以从靶向治疗中获益。然而靶向治疗耐药性一直是黑色素瘤治疗急需解决的问题，耐药性的出现严重影响了疗效，因此对于耐药机制的探索和研究十分必要。
- 恶性黑色素瘤 /
- 靶向治疗 /
- 耐药机制
Abstract: Malignant melanoma is an extremely aggressive tumor that can be surgically treated in its early stage. In advanced stages, the invasive and proliferative capabilities of melanoma cells continue to increase, and traditional treatment methods such as radiotherapy, chemotherapy, and immunotherapy have limited efficacy, resulting in poor patient prognosis. Due to the presence of mutations in multiple molecular pathways in malignant melanoma, targeted therapy is now regarded as a more viable treatment option for patients with advanced malignant melanoma, with most patients benefiting from it. However, the development of drug resistance to targeted therapy has always been a serious challenge, as the emergence of resistance limits the efficacy. Therefore, it is necessary to explore the mechanism and drug resistance of targeted therapy of malignant melanoma.
- Malignant melanoma /
- Targeted therapy /
- Drug resistance mechanisms

HTML全文

参考文献(47)

[1]	Long G V,Swetter S M,Menzies A M,et al. Cutaneous melanoma[J]. Lancet,2023,402(10400):485-502. doi: 10.1016/S0140-6736(23)00821-8
[2]	Patel H,Yacoub N,Mishra R,et al. Current advances in the treatment of BRAF-mutant melanoma[J]. Cancers (Basel),2020,12(2):482. doi: 10.3390/cancers12020482
[3]	Aya F,Lanuza-Gracia P,Gonz á lez-P é rez A,et al. Genomic deletions explain the generation of alternative BRAF isoforms conferring resistance to MAPK inhibitors in melanoma[J]. Cell Rep,2024,43(4):114048. doi: 10.1016/j.celrep.2024.114048
[4]	Gerosa L,Chidley C,Fröhlich F,et al. Receptor-driven ERK pulses reconfigure MAPK signaling and enable persistence of drug-adapted BRAF-mutant melanoma cells[J]. Cell Syst,2020,11(5):478-494. doi: 10.1016/j.cels.2020.10.002
[5]	Boutros A,Croce E,Ferrari M,et al. The treatment of advanced melanoma: current approaches and new challenges[J]. Crit Rev Oncol Hematol,2024,196:104276. doi: 10.1016/j.critrevonc.2024.104276
[6]	Klobuch S,Seijkens T T P,Schumacher T N,et al. Tumour-infiltrating lymphocyte therapy for patients with advanced-stage melanoma[J]. Nat Rev Clin Oncol,2024,21(3):173-184. doi: 10.1038/s41571-023-00848-w
[7]	Fateeva A,Eddy K,Chen S. Current state of melanoma therapy and next steps: battling therapeutic resistance[J]. Cancers (Basel),2024,16(8):1571. doi: 10.3390/cancers16081571
[8]	Boz Er A B,Sheldrake H M,Sutherland M. Overcoming vemurafenib resistance in metastatic melanoma: Targeting integrins to improve treatment efficacy[J]. Int J Mol Sci,2024,25(14):7946. doi: 10.3390/ijms25147946
[9]	刘欣,张晓伟,罗志国. BRAF突变型黑色素瘤治疗进展[J]. 中国肿瘤临床,2022,49(10):487-491.
[10]	Menzies A M,Long G V. Dabrafenib and trametinib,alone and in combination for BRAF-mutant metastatic melanoma[J]. Clin Cancer Res,2014,20(8):2035-2043. doi: 10.1158/1078-0432.CCR-13-2054
[11]	Spagnolo F,Ghiorzo P,Orgiano L,et al. BRAF-mutant melanoma: Treatment approaches,resistance mechanisms,and diagnostic strategies[J]. Onco Targets Ther,2015,16;8:157-168.
[12]	Larkin J,Ascirto P A,Dréno B,et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma[J]. N Engl J Med,2014,371(20):1867-1876. doi: 10.1056/NEJMoa1408868
[13]	Robert C,Karaszewska B,Schachter J,et al. Improved overall survival in melanoma with combined dabrafenib and trametinib[J]. N Engl J Med,2015,372(1):30-39. doi: 10.1056/NEJMoa1412690
[14]	Long G V,Flaerty K T,Stroyakovskiy D,et al. Dabrafenib plus trametinib versus dabrafenib monotherapy in patients with metastatic BRAF V600E/K-mutant melanoma: long-term survival and safety analysis of a phase 3 study[J]. Ann Oncol,2017,28(7):1631-1639. doi: 10.1093/annonc/mdx176
[15]	王欣欣,田红旗. MEK抑制剂联合用药在黑色素瘤治疗中的应用研究进展[J]. 山东医药,2019,59(20):96-99.
[16]	Dummer R,Ascierto P A,Gogas H J,et al. Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): A multicentre,open-label,randomised phase 3 trial [J],Lancet Oncol,2018,19(5): 603-615.
[17]	Schadendorf D,Dummer R,Flaherty KT,et al. COLUMBUS 7-year update: A randomized,open-label,phase III trial of encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF V600E/K-mutant melanoma[J]. Eur J Cancer,2024,204:114073. doi: 10.1016/j.ejca.2024.114073
[18]	Morris E J,Jha S,Restaino C R,et al. Discovery of a novel ERK inhibitor with activity in models of acquired resistance to BRAF and MEK inhibitors[J]. Cancer Discov,2013,3(7):74250.
[19]	Bhagwat S V,McMillen W T,Cai S,et al. ERK inhibitor LY3214996 targets ERK pathway-driven cancers: A therapeutic approach toward precision medicine[J]. Mol Cancer Ther,2020,19(2):325-336. doi: 10.1158/1535-7163.MCT-19-0183
[20]	Shirley C A,Chhabra G,Amiri D,et al. Immune escape and metastasis mechanisms in melanoma: Breaking down the dichotomy[J]. Front Immunol,2024,15:1336023. doi: 10.3389/fimmu.2024.1336023
[21]	Zhu Z,Jin Y,Zhou J,et al. PD1/PD-L1 blockade in clear cell renal cell carcinoma: mechanistic insights,clinical efficacy,and future perspectives[J]. Mol Cancer,2024,23(1):146. doi: 10.1186/s12943-024-02059-y
[22]	Munir A Z,Gutierrez A,Qin J,et al. Immune-checkpoint inhibitor-mediated myocarditis: CTLA4,PD1 and LAG3 in the heart[J]. Nat Rev Cancer,2024,24(8):540-553. doi: 10.1038/s41568-024-00715-5
[23]	Schadendorf D,Van Akkooi ACJ,Berking C,et al. Melanoma[J]. Lancet,2018,392(10151):971-984. doi: 10.1016/S0140-6736(18)31559-9
[24]	Wolchok J D,Chiarion-Sileni V,Gonzalez R,et al. Long-term outcomes with nivolumab plus ipilimumab or nivolumab alone versus ipilimumab in patients with advanced melanoma[J]. J Clin Oncol,2022,40(2):127-137. doi: 10.1200/JCO.21.02229
[25]	Ribas A,Lawrence D,Atkinson V,et al. Combined BRAF and MEK inhibition with PD-1 blockade immunotherapy in BRAF-mutant melanoma[J]. Nat Med,2019,25(6):936-940. doi: 10.1038/s41591-019-0476-5
[26]	陈述,梅玲蔚. 恶性黑色素瘤的靶向药物治疗进展[J]. 现代医药卫生,2022,38(7):1184-1188.
[27]	Zhou S,Abdihamid O,Tan F,et al. KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST[J]. Cell Commun Signal,2024,22(1):153. doi: 10.1186/s12964-023-01411-x
[28]	Guo J,Carvajal R D,Dummer R,et al. Efficacy and safety of nilotinib in patients with KIT-mutated metastatic or inoperable melanoma: final results from the global,single-arm,phase II TEAM trial[J]. Ann Oncol,2017,28(6):1380-1387. doi: 10.1093/annonc/mdx079
[29]	谢永淳,邓思瑶,路顺. 黏膜黑色素瘤的免疫和靶向治疗研究进展[J]. 肿瘤预防与治疗,2022,35(8):751-758.
[30]	Shaw P,Dwivedi S K D,Bhattacharya R,et al. VEGF signaling: role in angiogenesis and beyond[J]. Biochim Biophys Acta Rev Cancer,2024,1879(2):189079. doi: 10.1016/j.bbcan.2024.189079
[31]	Perez D G,Suman V J,Fitch T R,et al. Phase 2 trial of carboplatin,weekly paclitaxel,and biweekly bevacizumab in patients with unresectable stage IV melanoma: A North Central Cancer Treatment Group study,N047A[J]. Cancer,2009,115(1):119-127. doi: 10.1002/cncr.23987
[32]	Gouda M A,Thein K Z,Hong D S. Tissue-agnostic targeting of neurotrophic tyrosine receptor kinase fusions: Current approvals and future directions[J]. Cancers (Basel),2024,16(19):3395. doi: 10.3390/cancers16193395
[33]	Tangella L P,Clark M E,Gray E S. Resistance mechanisms to targeted therapy in BRAF-mutant melanoma - A mini review[J]. Biochim Biophys Acta Gen Subj,2021,1865(1):129736. doi: 10.1016/j.bbagen.2020.129736
[34]	Czarnecka A M,Bartnik E,Fiedorowicz M,et al. Targeted therapy in melanoma and Mechanisms of Resistance[J]. Int J Mol Sci,2020,21(13):4576. doi: 10.3390/ijms21134576
[35]	Maertens O,Johnson B,Hollstein P,et al. Elucidating distinct roles for NF1 in melanomagenesis[J]. Cancer Discov,2013,3(3):338-349. doi: 10.1158/2159-8290.CD-12-0313
[36]	Zhou P,Meng X,Nie Z,et al. PTEN: An emerging target in rheumatoid arthritis?[J]. Cell Commun Signal,2024,22(1):246.
[37]	Paraiso K H,Xiang Y,Rebecca V W,et al. PTEN loss confers BRAF inhibitor resistance to melanoma cells through the suppression of BIM expression[J]. Cancer Res,2011,71(7):2750-2760. doi: 10.1158/0008-5472.CAN-10-2954
[38]	Shi H,Hugo W,Kong X,et al. Acquired resistance and clonal evolution in melanoma during BRAF inhibitor therapy[J]. Cancer Discov,2014,4(1):80-93. doi: 10.1158/2159-8290.CD-13-0642
[39]	Johannessen C M,Boehm J S,Kim S Y,et al. COT drives resistance to RAF inhibition through MAP kinase pathway reactivation[J]. Nature,2010,468(7326):968-972. doi: 10.1038/nature09627
[40]	Lehmann B D,Shaver T M,Johnson D B,et al. Identification of targetable recurrent MAP3K8 rearrangements in melanomas lacking known driver mutations[J]. Mol Cancer Res,2019,17(9):1842-1853. doi: 10.1158/1541-7786.MCR-19-0257
[41]	Kundu M,Butti R,Panda V K,et al. Modulation of the tumor microenvironment and mechanism of immunotherapy-based drug resistance in breast cancer[J]. Mol Cancer,2024,23(1):92. doi: 10.1186/s12943-024-01990-4
[42]	Liu H,Tang L,Li Y,et al. Nasopharyngeal carcinoma: current views on the tumor microenvironment's impact on drug resistance and clinical outcomes[J]. Mol Cancer,2024,23(1):20. doi: 10.1186/s12943-023-01928-2
[43]	Zhao K,Lu Y,Chen Y,et al. Transcripts 202 and 205 of IL-6 confer resistance to Vemurafenib by reactivating the MAPK pathway in BRAF(V600E) mutant melanoma cells[J]. Exp Cell Res,2020,390(2):111942. doi: 10.1016/j.yexcr.2020.111942
[44]	Zhao K,Lu Y,Chen Y,et al. Dual inhibition of MAPK and JAK2/STAT3 pathways is critical for the treatment of BRAF mutant melanoma[J]. Mol Ther Oncolytics,2020,18:100-108. doi: 10.1016/j.omto.2020.06.004
[45]	Comunanza V,Corà D,Orso F,et al. VEGF blockade enhances the antitumor effect of BRAFV600E inhibition[J]. EMBO Mol Med,2017,9(2):219-237. doi: 10.15252/emmm.201505774
[46]	Leiphrakpam P D,Are C. PI3K/Akt/mTOR signaling pathway as a target for colorectal Cancer Treatment[J]. Int J Mol Sci,2024,25(6):3178. doi: 10.3390/ijms25063178
[47]	Shi H,Hugo W,Kong X,et al. Acquired resistance and clonal evolution in melanoma during BRAF inhibitor therapy[J]. Cancer Discov,2014,4(1):80-93. doi: 10.1158/2159-8290.CD-13-0642

计量

文章访问数: 476
HTML全文浏览量: 306
PDF下载量: 39
被引次数: 0

姓名
邮箱
手机号码
标题
留言内容
验证码

留言板

恶性黑色素瘤靶向治疗及其耐药机制研究进展

doi: 10.12259/j.issn.2095-610X.S20250222

作者简介:
刘一帆（1998～），男，山东临沂人，在读硕士研究生，主要从事肿瘤发生发展机制研究工作

通讯作者:
杨志惠，E-mail：yzhih73@swmu.edu.cn

计量

Research Progress on Targeted Therapy and Resistance Mechanisms of Malignant Melanoma

计量

目录

[1]	李志霄, 郑霞, 李春玲, 刘庆圣, 张衡. miR-205-5p靶向ERBB3调控PI3K/AKT/mTOR通路抑制血管生成在痔疮中的分子机制, 昆明医科大学学报. doi: 10.12259/j.issn.2095-610X.S20240604
[2]	丁慧, 周庆, 冯汝舟, 周妮, 张石楠, 刘娟. 清除儿童外源性牙面黑色素两种方法的疗效比较, 昆明医科大学学报. doi: 10.12259/j.issn.2095-610X.S20230801
[3]	方翠华, 潘茂华, 周隆参, 覃宇城, 黄亚铭, 马佳, 陈熙, 杨照青. 黑色素瘤免疫治疗现状及研究进展, 昆明医科大学学报. doi: 10.12259/j.issn.2095-610X.S20230519
[4]	李露, 田云粉. 肠道菌群与儿童非酒精性脂肪性肝病的研究进展, 昆明医科大学学报. doi: 10.12259/j.issn.2095-610X.S20230708
[5]	李婷, 郭维华. 糖酵解重编程在口腔鳞状细胞癌中的研究进展, 昆明医科大学学报. doi: 10.12259/j.issn.2095-610X.S20230611
[6]	李晨希, 查卓岑, 李娜, 罗琳, 杨扬, 陈文林. 三阳性乳腺癌的强化辅助治疗方案选择, 昆明医科大学学报. doi: 10.12259/j.issn.2095-610X.S20231020
[7]	陆小华, 袁洪新. BTLA、CTLA-4基因多态性与肝癌TACE联合靶向治疗疗效及预后相关性, 昆明医科大学学报. doi: 10.12259/j.issn.2095-610X.S20230927
[8]	张海霞, 李磊, 金磊, 叶沛婧, 孙传政. 云南省肿瘤医院1 203例黑色素瘤临床分析, 昆明医科大学学报. doi: 10.12259/j.issn.2095-610X.S20220808
[9]	罗巧, 石宏, 王绍波. α7-烟碱乙酰胆碱受体在肺癌发生、发展及治疗中的作用, 昆明医科大学学报. doi: 10.12259/j.issn.2095-610X.S20220226
[10]	吴希兰, 沈红, 石素胜, 张智慧, 郭蕾, 王芳. PD-L1、BRAF^V600E、CD68蛋白表达及肿瘤浸润淋巴细胞在恶性黑色素瘤诊断中的意义, 昆明医科大学学报. doi: 10.12259/j.issn.2095-610X.S20220923
[11]	刘宏伟, 姚建辉, 刘鹏军, 李卫民. miR-145靶向PDCD4在缺血性脑卒中的作用机制, 昆明医科大学学报.
[12]	朱中山, 严文辉, 李小兵, 杨洲, 白鹏. 200例肺腺癌脑转移患者驱动基因突变情况及预后关系, 昆明医科大学学报.
[13]	胡玉崇, 陆景坤, 崔梦瑶. PTEN及Caspase-3可能参与卵巢癌铂类耐药的机制, 昆明医科大学学报.
[14]	钱璐, 边莉. 肺癌EGFR基因突变以及靶向药物耐药机制的研究进展, 昆明医科大学学报.
[15]	周喆焱. E-cadherin对非小细胞肺癌的转移和靶向治疗的影响, 昆明医科大学学报.
[16]	卿晨. 恶性肿瘤化疗耐药及克服耐药的研究, 昆明医科大学学报.
[17]	张振光. 椎管内恶性黑色素细胞瘤1例报道, 昆明医科大学学报.
[18]	许克东. Cytohesin-2在肝癌细胞株中的表达及调控Hep3B细胞增殖作用的研究, 昆明医科大学学报.
[19]	陈贤玉. 曲妥珠单抗1治疗HER-2过表达乳腺癌的研究进展, 昆明医科大学学报.
[20]	陈永生. 阴茎恶性黑色素瘤并双侧腹股沟淋巴结转移1例报道, 昆明医科大学学报.

留言板

恶性黑色素瘤靶向治疗及其耐药机制研究进展

doi: 10.12259/j.issn.2095-610X.S20250222

作者简介: 刘一帆（1998～），男，山东临沂人，在读硕士研究生，主要从事肿瘤发生发展机制研究工作

通讯作者: 杨志惠，E-mail：yzhih73@swmu.edu.cn

计量

出版历程

Research Progress on Targeted Therapy and Resistance Mechanisms of Malignant Melanoma

计量

出版历程

目录

作者简介:
刘一帆（1998～），男，山东临沂人，在读硕士研究生，主要从事肿瘤发生发展机制研究工作

通讯作者:
杨志惠，E-mail：yzhih73@swmu.edu.cn