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世界临床病例杂志 2023年第27期11卷 6664-6669页

作者： Sang Jae Lee Si-Youn Song Min Kyoung Kim Hyung Gyun Na Chang Hoon Bae Yong-Dae Kim Yoon Seok Choi Department of Otorhinolaryngology-Head and Neck Surgery College of MedicineYeungnam UniversityDaegu 42415South Korea Division of Hematology-Oncology Department of Internal MedicineCollege of MedicineYeungnam UniversityDaegu 42415South Korea Regional Center for Respiratory Diseases Yeungnam University Medical CenterDaegu 42415South Korea

BACKGROUND Anaplastic thyroid cancer(ATC)is a rare but aggressive type of thyroid carcinoma.BRAF V600E-mutation,which is found in 10%-50%of ATCs,is associated with poor prognosis.A recent clinical trial reported a substantial clinical benefit of concomitant treatment of dabrafenib(BRAF inhibitor)and Trametinib(MEK inhibitor)for treating BRAF V600E-mutant ATC.However,reports on patients with ATC treated with this regimen following surgery are lacking.CASE SUMMARY We report the case of a 63-year-old female patient diagnosed with BRAF V600Emutant ATC.Following three surgeries—total thyroidectomy,total laryngectomy,and neck dissection—she was diagnosed with lung metastasis during follow-up.The metastatic ATC was successfully treated with dabrafenib and Trametinib.The patient achieved a complete response at the 32-mo follow-up.CONCLUSION Adjuvant chemotherapy with dabrafenib plus Trametinib is efficacious for treatment and prevention of recurrent ATC with BRAF mutation following surgery.

关键词： Thyroid carcinoma Anaplastic BRAF Dabrafenib Trametinib Chemotherapy Adjuvant Case report

Radiation recall dermatitis with dabrafenib and Trametinib: A case report

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World Journal of Clinical Cases 2020年第3期8卷 522-526页

作者： Mesut Yilmaz Ugur Celik Seyhan Hascicek Medical Oncology Department Bakirköy Dr.Sadi Konuk Training and Research HospitalIstanbul 34144Turkey Dermatology Department Medipol Kosuyolu HospitalIstanbul 34134Turkey Pathology Department Sisli Hamidiye Etfal Training and Research HospitalIstanbul 34134Turkey

BACKGROUND Radiation recall dermatitis has been defined as the "recalling" by skin of previous radiation exposure in response to the administration of certain response-inducing drugs. Although the phenomenon is relatively well known in the medical world,an exact cause has not been documented.CASE SUMMARY Here, we report the rare occurrence of radiation recall dermatitis after palliative radiotherapy for bone metastases in a metastatic melanoma patient treated with a combination of dabrafenib and Trametinib.CONCLUSION We present a case of radiation recall dermatitis after completion of palliative radiotherapy while being treated with a combination of dabrafenib and Trametinib. This is a very rare toxic event, and there is insufficient data to describe prevention strategies. Increased awareness and reporting of cases will help to better explain the association between targeted therapy and the radiation recall phenomenon.

关键词： Radiation recall dermatitis Melanoma Radiotherapy Dabrafenib Trametinib Case report

Trametinib and dactolisib but not regorafenib exert antiproliferative effects on rat pancreatic stellate cells

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Hepatobiliary & Pancreatic Diseases International 2015年第6期14卷 642-650页

作者： Laura Witteck Robert Jaster Department of Medicine Ⅱ Division of GastroenterologyRostock University Medical Center

BACKGROUND： Modulation of the stroma response is considered a promising approach for the treatment of chronic pancreatitis and pancreatic cancer. The aim of this study was to evaluate the effects of three clinically available small molecule kinase inhibitors, regorafenib, Trametinib and dactolisib, on effector functions of activated pancreatic stellate cells （PSCs）, which play a key role in pancreatic fibrosis.

关键词： stellate cell biology pancreatic cancer chronic pancreatitis Trametinib dactolisib

Synthetic lethal short hairpin RNA screening reveals that ring finger protein 183 confers resistance to Trametinib in colorectal cancer cells

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Chinese Journal of Cancer 2017年第12期36卷 726-736页

作者： Rong Geng Xin Tan Zhixiang Zuo Jiangxue Wu Zhizhong Pan Wei Shi Ranyi Liu Chen Yao Gaoyuan Wang Jiaxin Lin Lin Qiu Wenlin Huang Shuai Chen State Key Laboratory of Oncology in South China Collaborative Innovation Center of Cancer MedicineSun Yat-sen University Cancer Center651 Dongfeng Road EastGuangzhou 510507GuangdongP.R.China Department of Experimental Research Sun Yat-sen University Cancer CenterGuangzhou 510060GuangdongP.R.China Department of Colorectal Surgery Sun Yat-sen University Cancer CenterGuangzhou 510060GuangdongP.R.China Guangdong Esophageal Cancer Institute Sun Yat-sen University Cancer CenterGuangzhou 510060GuangdongP.R.China Guangdong Provincial Key Laboratory of Tumor.Targeted Drugs and Guangzhou Enterprise Key Laboratory of Gene Medicine Guangzhou Doublle Bioproducts Co.Ltd.Guangzhou 510507GuangdongP.R.China

Background: The mitogen-activated extracellular signal-regulated kinase 1/2(MEK1/2) inhibitor Trametinib has shown promising therapeutic effects on melanoma, but its efficacy on colorectal cancer(CRC) is limited. Synthetic lethality arises with a combination of two or more separate gene mutations that causes cell death, whereas individual mutations keep cells alive. This study aimed to identify the genes responsible for resistance to Trametinib in CRC cells,using a synthetic lethal short hairpin RNA(shRNA) screening approach.Methods: We infected HT29 cells with a pooled lentiviral shRNA library and applied next-generation sequencing to identify shRNAs with reduced abundance after 8-day treatment of 20 nmol/L Trametinib. HCT116 and HT29 cells were used in validation studies. Stable ring finger protein 183(RNF183)-overexpressing cell lines were generated by pcDNA4-myc/his-RNF183 transfection. Stable RNF 183-knockdown cell lines were generated by infection of lentiviruses that express RNF183 shRNA, and small interference RNA(siRNA) was used to knock down RNF183 transiently.Quantitative real-time PCR was used to determine the mRNA expression. Western blotting, immunohistochemical analysis, and enzyme-linked immunosorbent assay(ELISA) were used to evaluate the protein abundance. MTT assay,colony formation assay, and subcutaneous xenograft tumor growth model were used to evaluate cell proliferation.Results: In the primary screening, we found that the abundance of RNF183 shRNA was markedly reduced after treatment with Trametinib. Trametinib induced the expression of RNF183, which conferred resistance to drug-induced cell growth repression and apoptotic and non-apoptotic cell deaths. Moreover, interleukin-8(IL-8) was a downstream gene of RNF183 and was required for the function of RNF183 in facilitating cell growth. Additionally, elevated RNF183 expression partly reduced the inhibitory effect of Trametinib on IL-8 expression. Finally, xenograft tumor model showed the synergism of RNF183 knockdown and Trametinib in repres

关键词： Synthetic lethal Colorectal cancer Ring finger protein 183 Mitogen-activated extracellular signalregulated kinase 1/2 Trametinib

Asian Case of Metastatic Melanoma in Which a Complete Response Was Maintained after Discontinuation of Dabrafenib and Trametinib

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Journal of Cosmetics, Dermatological Sciences and Applications 2020年第2期10卷 55-58页

作者： Rikako Deno Atsushi Tanemura Madoka Takafuji Yuma Hanaoka Eiji Kiyohara Noriko Arase Mari Wataya-Kaneda Manabu Fujimoto Department of Dermatology Graduate School of Medicine Osaka University Suita Osaka Japan

A 54-year-old man diagnosed with metastatic melanoma of the right inguinal node with occult primary developed liver and bone metastases. The combination of dabrafenib plus Trametinib was initiated, and a complete response (CR) was achieved 24 months after starting treatment. One month later, the target therapy was discontinued at the patient’s decision, and he has remained free from progression for 21 months since discontinuation. To the extent of our knowledge, real-world data in Asian melanoma concerning the discontinuation of dabrafenib plus Trametinib after achieving CR have not been published;therefore, our case is a meaningful one for considering to cease target drugs and to rescue their financial toxicity.

关键词： Metastatic Melanoma Dabrafenib Trametinib Complete Response Discontinuation

Repurposing econazole as a pharmacological autophagy inhibitor to treat pancreatic ductal adenocarcinoma

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Acta Pharmaceutica Sinica B 2022年第7期12卷 3085-3102页

作者： Ningna Weng Siyuan Qin Jiayang Liu Xing Huang Jingwen Jiang Li Zhou Zhe Zhang Na Xie Kui Wang Ping Jin Maochao Luo Liyuan Peng Edouard C.Nice Ajay Goel Suxia Han Canhua Huang Qing Zhu Department of Abdominal Oncology West China Hospital of Sichuan UniversityChengdu 610041China State Key Laboratory of Biotherapy and Cancer Center West China HospitalWest China School of Basic Medical Sciences&Forensic MedicineSichuan UniversityCollaborative Innovation Center for BiotherapyChengdu 610041China Department of Pancreatic Surgery West China Hospital of Sichuan UniversityChengdu 610041China Department of Biochemistry and Molecular Biology Monash UniversityClaytonVIC 3800Australia Department of Molecular Diagnostics and Experimental Therapeutics Beckman Research Institute of City of HopeBiomedical Research CenterMonroviaCA 91016USA Department of Oncology the First Affiliated HospitalXi’an Jiaotong UniversityXi’an 710061China

Pancreatic ductal adenocarcinoma(PDAC)is characterized by the highest mortality among carcinomas.The pathogenesis of PDAC requires elevated autophagy,inhibition of which using hydroxychloroquine has shown promise.However,current realization is impeded by its suboptimal use and unpredictable toxicity.Attempts to identify novel autophagy-modulating agents from already approved drugs offer a rapid and accessible approach.Here,using a patient-derived organoid model,we performed a comparative analysis of therapeutic responses among various antimalarial/fungal/parasitic/viral agents,through which econazole(ECON),an antifungal compound,emerged as the top candidate.Further testing in cell-line and xenograft models of PDAC validated this activity,which occurred as a direct consequence of dysfunctional autophagy.More specifically,ECON boosted autophagy initiation but blocked lysosome biogenesis.RNA sequencing analysis revealed that this autophagic induction was largely attributed to the altered expression of activation transcription factor 3(ATF3).Increased nuclear import of ATF3 and its transcriptional repression of inhibitor of differentiation-1(ID-1)led to inactivation of the AKT/mammalian target of rapamycin(m TOR)pathway,thus giving rise to autophagosome accumulation in PDAC cells.The magnitude of the increase in autophagosomes was sufficient to elicit ER stress-mediated apoptosis.Furthermore,ECON,as an autophagy inhibitor,exhibited synergistic effects with Trametinib on PDAC.This study provides direct preclinical and experimental evidence for the therapeutic efficacy of ECON in PDAC treatment and reveals a mechanism whereby ECON inhibits PDAC growth.

关键词： Econazole Autophagy PDAC ATF3 AKT Organoid Trametinib Therapy

Pharmacological drug screening to inhibit uveal melanoma metastatic cells either via EGF-R, MAPK, mTOR or PI3K

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International Journal of Ophthalmology(English edition) 2022年第10期15卷 1569-1576页

作者： Stefan Kassumeh Sebastian Arrow AndréKafka Nikolaus Luft Siegfried G.Priglinger Armin Wolf Kirsten Eibl-Lindner Christian M.Wertheimer Department of Ophthalmology University HospitalLMU MunichMunich 80336Germany Department of Ophthalmology University HospitalUniversity UlmUlm 89075Germany

AIM: To screen five potential pharmacological substances specifically targeting EGF-R, MAPK, mTOR, or PI3K for their antiproliferative effects, possible impact on cell viability, as well as cell death rates on three different uveal melanoma metastasis cell lines in vitro. METHODS: Three different uveal melanoma metastasis cell lines(OMM2.5, OMM2.3, and OMM1), that originated from human hepatic and subcutaneous metastasis, were exposed to inhibitors of different targets: erlotinib(EGF-R), everolimus(mTOR), selumetinib(MAPK), Trametinib(MAPK) or the alkylphosphocholine erufosine(PI3K). Cell viability was assessed with a 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide(XTT) dye reduction assay after 24 h of treatment. Antiproliferative effects were evaluated separately after a 72-hour incubation of the cells with the pharmacological substance. Subsequently, the IC_(50) was calculated. Tumor cell death was investigated using a double stain apoptosis detection assay. RESULTS: Selumetinib, Trametinib, and erufosine significantly decreased cell viability of all OMM cell lines(PTrametinib showed a significant inhibition of cell proliferation(P<0.05). Everolimus and erlotinib solely inhibited cell proliferation at the used concentrations(P<0.05). Besides an increase of necrotic cells after erufosine treatment(P<0.001), no changes in the number of dead cells for the other substances were observed.CONCLUSION: The preliminary drug screening demonstrates five new candidates, successfully targeting the canonical MAPK/ERK and PI3K/AKT/m TOR pathways in uveal melanoma metastasis cells in vitro. Hence, these findings provide an experimental basis to explore future single or combined therapy strategies for metastatic uveal melanoma.

关键词： uveal melanoma selumetinib Trametinib erufosine erlotinib

基于TLR7激动剂的FZD7疫苗抗小鼠结直肠癌的作用研究

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基于TLR7激动剂的FZD7疫苗抗小鼠结直肠癌的作用研究

作者：贺轩昂深圳大学

学位级别：硕士

目的:结直肠癌是最常见的消化道恶性肿瘤之一,其发病率和致死率在全球恶性肿瘤排名中均名列前茅。MEK抑制剂Trametinib对含B-Raf和Ras突变的肿瘤细胞的抑制效果明显,尤其是对于黑色素瘤和人结直肠癌细胞系有很强的抑制作用。但长期使用... 详细信息

目的:结直肠癌是最常见的消化道恶性肿瘤之一,其发病率和致死率在全球恶性肿瘤排名中均名列前茅。MEK抑制剂Trametinib对含B-Raf和Ras突变的肿瘤细胞的抑制效果明显,尤其是对于黑色素瘤和人结直肠癌细胞系有很强的抑制作用。但长期使用MEK抑制剂治疗结直肠癌会不可避免导致耐药性的产生。因此,将MEK抑制剂与其他药物联合使用以增强结直肠癌的治疗效果将成为一种新型治疗方式。Wnt通路与癌症的发生和进展极为密切。FZD7作为Wnt信号通路的主要受体之一,通过与Wnt配体结合来激活下游的信号传导通路。研究表明胞外的FZD7肽段可通过阻断FZD7的功能,抑制经典的Wnt/β-catenin通路,从而达到治疗肿瘤的目的。Toll样受体是连接固有免疫和适应性免疫的桥梁,而TLR7激动剂能有效的激活免疫从而发挥抗瘤作用。在本课题中,我们使用本实验室自主合成的含双键SZU-138作为TLR7小分子激动剂,与公司合成的富含半胱氨酸的FZD7胞外肽(FZD-54)再加上佐剂氢氧化铝Al(OH),按一定比例混合搅拌后形成多肽疫苗,然后再联合靶向药曲美替尼(Trametinib,属于MEK抑制剂)进行抗瘤效果的评估。我们期望在靶向治疗肿瘤的同时也能激活免疫系统。本课题通过体内外实验,系统性的评价了该疫苗的免疫活性和抗肿瘤活性,为研发新型多肽疫苗提供了新思路。方法:(1)用化学方法合成全新的、高纯度的TLR7激动剂SZU-138,并用质谱进行结构鉴定。(2)用HEK-Blue hTLR7报告细胞系证明SZU-138的激动效应。(3)用ELISA方法检测SZU-138和FZD7胞外肽在体外对免疫细胞的免疫激活效果。(4)用CCK8方法检测疫苗和Trametinib对CT26.WT的抑制效果。(5)Western Blot检测FZD7胞外肽对Wnt信号通路的抑制作用。(6)建立小鼠结直肠癌模型,验证多肽疫苗和Trametinib的联合抗肿瘤效果。(7)用流式细胞术分析多肽疫苗对浸润性T细胞的影响。(8)用免疫组化和免疫荧光等方法分析多肽疫苗对浸润性T细胞的影响。结果:(1)SZU-138是一种选择性强且高效的TLR7激动剂,在体外能刺激免疫细胞分泌大量免疫因子。(2)FZD7多肽与SZU-138混合形成的疫苗在体外也能刺激免疫细胞分泌大量细胞因子,且激活免疫的能力要强于SZU-138。(3)疫苗与Trametinib联用时既对癌细胞有一定的抑制作用,同时对正常细胞的抑制要低于Trametinib单独使用时对正常细胞的抑制,是更具优势的用药方式。(4)在小鼠结直肠癌肿瘤模型中,多肽疫苗可激活小鼠体内免疫,抑制肿瘤生长。其与Trametinib以及αPD-1联用后,对结直肠癌细胞的抑制作用得到增强,并延长荷瘤小鼠的生存周期,发挥比单独用药时更好的治疗效果。结论:新合成的SZU-138是有效的TLR7激动剂,其与FZD7多肽混合形成的多肽疫苗在体内外均有良好的免疫激活效果,能有效抑制肿瘤生长。该疫苗与Trametinib以及αPD-1联用后能进一步抑制肿瘤生长,并延长荷瘤小鼠的生存周期,发挥更好的治疗效果。本课题首次通过将MEK抑制剂和肿瘤干细胞FZD7疫苗联合的治疗实验,验证了此设计的有效性,为难治性结肠癌的免疫治疗提供了新方向。

关键词： TLR7激动剂 Frizzled-7 Wnt/β-catenin信号通路 Trametinib 免疫疗法

联合用药逆转结直肠癌细胞原发和获得性曲美替尼耐受的分子机制研究

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联合用药逆转结直肠癌细胞原发和获得性曲美替尼耐受的分子机制研...

作者：陈俊俊山西医科大学

学位级别：硕士

背景:肿瘤靶向药物可以通过干扰肿瘤发生和发展所需信号通路中的特定分子来阻断肿瘤细胞的生长。与传统化疗药物不同,靶向治疗药物有疗效高、毒副作用少的优点,但在临床实践中,原发和获得性耐药的问题限制了靶向治疗的有效性,成为精准... 详细信息

背景:肿瘤靶向药物可以通过干扰肿瘤发生和发展所需信号通路中的特定分子来阻断肿瘤细胞的生长。与传统化疗药物不同,靶向治疗药物有疗效高、毒副作用少的优点,但在临床实践中,原发和获得性耐药的问题限制了靶向治疗的有效性,成为精准医学及个体化治疗的障碍。Trametinib的作用靶点是MEK1/2,有研究报道,使用Trametinib治疗结直肠癌的患者在一段时间后会出现耐药现象。因此,研究Trametinib耐受的分子机制,设计逆转耐药的治疗策略至关重要。目前常用的方案之一是联合用药,这可以在一定程度上甚至完全逆转靶向药物的耐受现象。课题组前期通过药物敏感性筛选实验发现,具有KRAS基因突变的结直肠癌细胞SW480和CW2对Trametinib原发性耐受。针对这一耐药问题,我们将进行药物组合筛选,寻找具有协同作用且能够逆转结直肠癌细胞原发和获得性Trametinib耐受的药物组合,并分析逆转耐药的分子机制。本研究将为临床结直肠癌靶向治疗药物的选择提供一定参考依据。目的:筛选与Trametinib具有协同作用的药物组合,分析药物组合对原发和获得性Trametinib耐受结直肠癌细胞功能的影响,探讨细胞耐受Trametinib及药物组合逆转耐受的分子机制。方法:1.Chou-Talalay法筛选具有协同作用的药物组合利用MTT实验筛选具有协同作用的药物组合,“CompuSyn”软件计算得出联合指数(combination index,CI),定量描述联合用药的协同作用(CI1)。2.获得性Trametinib耐药细胞模型RKO-R的建立利用浓度梯度递增法建立耐药细胞模型,亲代RKO细胞依次在含有0.01,0.05和0.10μM的培养基中生长至少三个月。用MTT实验、克隆形成实验和流式细胞术检测耐药细胞株和亲代细胞的差异,判断是否成功建立了耐药细胞模型。3.联合用药对细胞功能的影响设置空白对照组、不同浓度的单药组和联合用药组,克隆形成实验检测药物对结直肠癌细胞SW480、CW2和RKO-R增殖能力的影响,western blot检测凋亡相关蛋白Cleaved-PARP表达的变化。4.Trametinib耐药及联合用药的分子机制研究Western blot技术检测Trametinib处理不同时间对MAPK和PI3K-AKT信号通路蛋白表达的影响。然后检测Trametinib和GSK2126458药物组合处理后上述通路蛋白表达的变化。结果:1.筛选出具有协同作用的药物组合Trametinib和GSK2126458,该组合在原发性Trametinib耐药细胞株SW480、CW2和获得性Trametinib耐药细胞株RKO-R中的CI值均小于1。2.与对照组和单药组相比,联合用药处理结直肠癌细胞后,细胞克隆形成能力降低,克隆形成抑制率增加,Cleaved-PARP的表达水平上调。3.Trametinib处理SW480细胞后,虽然ERK磷酸化水平受到抑制,但IGF1R和AKT的磷酸化水平上调;Trametinib处理CW2细胞后,ERK的磷酸化水平下调,但AKT的磷酸化水平上调。Trametinib处理RKO-R细胞后,ERK和AKT的磷酸化水平均未发生明显变化。4.在SW480、CW2和RKO-R细胞中,联合用药使ERK和AKT的磷酸化水平降低,不仅抑制了MAPK通路,同时阻断了PI3K-AKT通路。结论:Trametinib在抑制MAPK通路的同时,可激活旁路PI3K-AKT信号通路,这可能是结直肠癌细胞原发和获得性Trametinib耐受的分子机制之一。Trametinib和GSK2126458联合用药能通过同时抑制MAPK和PI3K-AKT通路来逆转该耐药现象,并能抑制结直肠癌细胞的增殖,促进凋亡。

关键词：结直肠癌 Trametinib 靶向药物耐药联合用药协同作用·

MEK inhibitors for the treatment of extracranial arteriovenous malformations

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中国整形与重建外科(英文) 2023年第3期5卷 141-144页

作者： Zi’an Xu Jingwei Zhou Yuxi Chen Xi Yang Chen Hua Yunbo Jin Xiaoxi Lin Department of Plastic and Reconstructive Surgery Shanghai Ninth People’s HospitalShanghai Jiao Tong University School of MedicineShanghai 200011China

Arteriovenous malformations(AVMs)are serious congenital vascular anomalies in which the arteries connect directly with veins without capillaries.This condition will continue to worsen without proper intervention and cause ulcers,repeated hemorrhages,and even cardiac insufficiency.Primary treatment options for AVMs include surgery and interventional treatment;however,they are associated with high risk and recurrence rates.Recent studies revealed that excessive activation of the Ras/MAPK pathway can induce the formation and development of peripheral AVM,whereas MEK inhibitors can effectively control nidus progression,making them a potential novel treatment for AVM.This review provides an up-to-date overview of correlated laboratory and clinical research to provide information for further research and clinical practice.

关键词： Arteriovenous malformation MEK1 MEKi Trametinib MAPK