酪氨酸激酶抑制剂在恶性黑素瘤分子靶向治疗中的进展

恶性黑素瘤是一种异质性肿瘤,不同发病部位或不同组织学类型,可能存在不同的基因和信号转导途径的异常.因此,针对异常基因、信号通路的靶向治疗药物的发明和临床应用为晚期黑素瘤患者的个性化治疗提供了新的选择.中国人最常见的黑素瘤是肢端型,该型黑素瘤中最常见的异常基因是c-kit基因.针对c-kit基因的靶向药物酪氨酸激酶抑制剂在治疗晚期黑素瘤方面已有较多体外研究及临床观察.主要介绍酪氨酸激酶抑制剂中的受体酪氨酸激酶抑制剂、多靶点酪氨酸激酶抑制剂和非受体酪氨酸激酶抑制剂3类药物的药理作用机制及国内外治疗黑素瘤的研究进展,以及酪氨酸激酶抑制剂的常见不良反应.     

黑素瘤相关MicroRNAs的研究进展

近年来发现MicroRNAs可通过膜受体酪氨酸蛋白激酶通路、P13K-AKT通路、P16INK4ACDK4/6-RB通路、小眼相关转录因子、p53-miR-149-3p-GSK3ix-Mcl-1通路影响黑素瘤的生物学行为,MicroRNAs及其靶基因相关通路的研究对黑素瘤的早期诊断、预后判断以及黑素瘤的靶向治疗具有重要的意义。     

Notch信号在黑素瘤发病机制中的研究进展

恶性黑素瘤是皮肤科恶性肿瘤之一,具有高度侵袭性和转移能力,致死率高,预后极差.目前认为发病与多个异常信号转导通路相关,但具体机制尚未阐明.Notch信号通路中多个受体及配体通过参与肿瘤血管再生、改变肿瘤细胞黏附性等行为参与黑素瘤的发生和转移,并与肿瘤发生有关的其他途径中的细胞相互作用,从而影响黑素瘤的命运.     

寻常型天疱疮信号通路研究进展

 寻常型天疱疮（PV）是一种罕见的自身免疫性大疱性皮肤病,其病理生理特征是自身抗体与桥粒芯蛋白（Dsg）结合导致棘层松解。尽管关于天疱疮发病机制信号通路的研究越来越多,但目前信号通路在天疱疮发病机制的作用尚未明确。p38丝裂原活化蛋白激酶（p38MAPK）、蛋白激酶C（PKC）和表皮生长因子受体（EGFR）等信号通路的活性改变被认为与PV发病密切相关。本文就相关信号通路阐述PV发病机制,为其寻找有效靶向药物治疗提供新的思路。     

黑素瘤发病机制相关蛋白的研究进展

黑素瘤是高死亡率的皮肤肿瘤,鉴定出与黑素瘤发病及进展相关的蛋白质有助于阐明黑素瘤的发病机制,临床上应早期诊断以提高疗效.近年来,比较蛋白组学、蛋白质表达谱等多种蛋白质组学研究方法应用于黑素瘤发病机制的研究,有助于明确相关细胞信号通路蛋白的功能,阐明肿瘤耐药机制、发现可能的肿瘤标记物以利于早期诊断、判断疗效和预后.     

皮肤黑素瘤的分子检测和靶向治疗

黑素瘤的诊断和治疗是重要的临床课题。黑素瘤的组织学形态变异很多,与某些色素细胞痣之间存在中间型的组织形态学交叉,有时病理诊断相当困难。分子病理学的进展为皮肤黑素瘤的确诊提供了新的方法,同时也为黑素瘤的临床治疗提供了有价值的依据。BRAF,KIT,NRAS,HRAS等基因参与黑素瘤的发生和进展的MAPK通路和Akt/PI3K通路。DNA测序、外显子组测序、FISH技术、免疫组织化学技术可以检测黑素瘤相关的分子变化。针对黑素瘤发生分子通路的靶向治疗将使患者受益。     

儿童黑素瘤临床研究进展

儿童黑素瘤较为罕见, 不同亚型的肿瘤存在发病机制的差异。部分肿瘤临床表现并不典型, 成人黑素瘤诊断标准可能不完全适用于儿童。手术是一线治疗手段, 具体切缘范围可小于成人。近年来黑素瘤的免疫治疗、靶向治疗等治疗手段迅速发展, 但相关药物很少获批儿童适应证。儿童黑素瘤治疗的大样本研究也较少, 但有文献报道相关药物的应用。本文综述儿童黑素瘤发病机制、临床表现和治疗的相关进展, 以期为儿童黑素瘤的诊治提供参考。     

黑素瘤相关基因研究进展

利用二代高通量测序技术对黑素瘤基因进行测序分析,以找出关键突变位点进行靶向治疗是当前的研究热点.黑素瘤基因突变特点是:基因突变负荷大,丝裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)信号传导通路上关键基因突变和大量非编码基因突变,不同种族和组织学类型黑素瘤基因突变差异大....     

泛素连接酶在皮肤黑素瘤的研究进展

皮肤黑素瘤是一种起源于皮肤黑素细胞的恶性肿瘤,具有高度增殖性和侵袭性,并常发生转移.尽管近年来皮肤恶性黑素瘤的治疗取得很大进展,但晚期黑素瘤患者预后依然很差.泛素蛋白酶体系统可通过调节细胞内蛋白对各种生理过程进行调控,泛素连接酶是泛素化过程中识别底物特异性的酶,可作为癌基因或抑癌基因参与黑素瘤发病机制,能够调节各种不同的信号通路和多种在黑素瘤发展中起重要作用的蛋白.因此,针对泛素连接酶的分子靶向治疗是目前研究黑素瘤的热点之一.     

黑素瘤核因子-κB活性的研究进展

黑素瘤是一种侵袭性的皮肤肿瘤,人类黑素瘤中存在核因子-κB的上调,异常的核因子-κB信号通路参与黑素瘤增殖、凋亡及肿瘤转移、血管生成等病理生理进程,导致基因异常表达,加速病情的进展.核因子-κB信号转导通路、关键调节因子如TNFR/TRADD/TRAF、TRAIL/TRAILR、FasR/FasL/FAP-1及基因突变等在黑素瘤的发生发展中起重要作用.因此,核因子-κB信号通路的研究有可能为治疗黑素瘤提供新的思路和方法.     

Vertical inhibition of the mTORC1/mTORC2/PI3K pathway shows synergistic effects against melanoma in vitro and in vivo

The phosphatidyl inositol 3-kinase/mammalian target of rapamycin (PI3K/mTOR) pathway has been shown to be involved in the development of melanoma. PI-103 is a kinase inhibitor blocking PI3K class IA and mTOR complex 1 and 2. Here, we studied the effect of targeting the PI3K/mTORC1/mTORC2 pathway by PI-103 and rapamycin in melanoma cells and in a melanoma mouse model. Dual targeting of PI3K and mTOR by PI-103 induced apoptosis and cell-cycle arrest, and inhibited viability of melanoma cells in vitro. Combined treatment with PI-103 and the prototypic mTORC1 inhibitor rapamycin led to the synergistic suppression of AKT and ribosomal S6 protein phosphorylation and to the induction of apoptosis. In vivo, PI-103 and rapamycin displayed only modest single-agent activity, but the combination significantly reduced the tumor growth compared with both single agents. These data show that blocking the PI3K/mTORC1/mTORC2 pathway using the combination of two distinct small-molecule inhibitors ("vertical inhibition") leads to superior efficacy against malignant melanoma in vitro and in vivo.     

微小RNA与银屑病发病相关信号转导通路关联的研究

细胞通过细胞间各种信号分子的活化来完成信号传导,从而控制细胞的生长、分化和凋亡.细胞间信号转导的异常经常是疾病发生的原因.银屑病的发病与多个信号转导通路的异常有关,主要丝裂原活化蛋白激酶信号转导通路、非受体酪氨酸蛋白激酶Janus激酶/信号转导和转录激活因子通路、肿瘤坏死因子α信号转导通路、磷脂酰肌醇3-激酶/蛋白激酶B信号转导通路,而这些通路的异常通常又与细胞转录后调控因子微小RNA有关.     

Targeted molecular therapy in melanoma

Immunotherapy and chemotherapy benefit few patients with metastatic melanoma, and even fewer experience durable survival benefit. These poor results may come from treating all melanomas as though they are biologically homogeneous. Recently, it has been shown that targeting specific activated tyrosine kinases (oncogenes) can have striking clinical benefits in patients with melanoma. In 2002, a V600E mutation of the BRAF serine/threonine kinase was described as present in more than 50% of all melanomas. The mutation appeared to confer a dependency by the melanoma cancer cell on activated signaling through mitogen-activated protein kinase pathway. The frequency and focality of this mutation (>95% of all BRAF mutations being at V600 position) suggested its importance in melanoma pathophysiology and potential as a target for therapy. The recent results of a phase 1 study with PLX4032/RG7204, a small molecule RAF inhibitor, confirm this hypothesis. Mucosal and acral-lentiginous melanomas, comprising 3% of all melanomas, frequently harbor activating mutations of c-kit and drugs targeting this mutation seem to confer similar benefits for these types of tumors. Here we provide an overview of the targeted therapy development in melanoma with emphasis on BRAF inhibition because of its prevalence and possibility of transforming the care of many melanoma patients.     

KIT as an Oncogenic Driver in Melanoma: An Update on Clinical Development

Metastatic melanoma is a heterogenous disease that has served as a model for the development of both targeted therapy and immunotherapy. KIT-mutated melanoma represents a rare subset, most commonly arising from acral, mucosal, and chronically sun-damaged skin. Additionally, KIT alterations are enriched in the triple wild-type subtype of cutaneous melanoma. Activating alterations of KIT—a transmembrane receptor tyrosine kinase important for cell development, growth, and differentiation—have been shown to be critical to oncogenesis across many tumor subtypes. Following the successes of BRAF-targeted therapy in melanoma and KIT-targeted therapy in gastrointestinal stromal tumors, small-molecule tyrosine kinase inhibitors targeting KIT have been examined in KIT-mutated melanoma. KIT inhibitors that have been investigated in relevant clinical trials in advanced melanoma include imatinib, sunitinib, dasatinib, and nilotinib. In these studies, selected patients with KIT-mutated melanoma were shown to be responsive to therapy with KIT inhibition, especially patients with L576P and K642E mutations. This has led to the incorporation of KIT-targeted therapy in the National Comprehensive Cancer Network guidelines for systemic therapy for metastatic or unresectable melanoma. Current research and development efforts include novel KIT-targeted therapies and testing KIT inhibitors in combination with immunotherapy.

     

Galectin-3 and the skin

Galectin-3 is highly expressed in epithelial cells including keratinocytes and is involved in the pathogenesis of inflammatory skin diseases by affecting the functions of immune cells. For example, galectin-3 can contribute to atopic dermatitis (AD) by promoting polarization toward a Th2 immune response by regulating dendritic cell (DC) and T cell functions. In addition, galectin-3 may be involved in the development of contact hypersensitivity by regulating the migratory capacity of antigen presenting cells. Galectin-3 may act as a regulator of epithelial tumor progression and development through various signaling pathways, such as inhibiting keratinocyte apoptosis through regulation of the activation status of extracellular signal-regulated kinase (ERK) and activated protein kinase B (AKT). Galectin-3 is detected at different stages of melanoma development. In contrast, a marked decrease in the expression of galectin-3 is observed in non-melanoma skin cancers, such as squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). Galectin-3 may play an important role in tumor cell growth, apoptosis, cell motility, invasion, and metastasis. Galectin-3 may be a novel therapeutic target for a variety of skin diseases.     

Combined targeting of MAPK and AKT signalling pathways is a promising strategy for melanoma treatment

BACKGROUND: In melanoma, several signalling pathways are constitutively activated. Among them, the RAS/RAF/MEK/ERK (MAPK) and PI3K/AKT (AKT) signalling pathways are activated through multiple mechanisms and appear to play a major role in melanoma development and progression. OBJECTIVES: In this study, we examined whether targeting the MAPK and/or AKT signalling pathways would have therapeutic effects against melanoma. METHODS: Using a panel of pharmacological inhibitors (BAY 43-9006, PD98059, U0126, wortmannin, LY294002) we inhibited the MAPK and AKT signalling pathways at different levels and evaluated the effects on growth, survival and invasion of melanoma cells in monolayer and organotypic skin culture. RESULTS: Antiproliferative and proapoptotic effects of inhibitors alone in monolayer culture were disappointing and varied among the different cell lines. In contrast, combined targeting of the MAPK and AKT signalling pathways significantly inhibited growth and enhanced apoptosis in monolayer culture. To verify our data in a more physiological context we incorporated melanoma cells into regenerated human skin mimicking the microenvironment of human melanoma. Combinations of MAPK and AKT inhibitors completely suppressed invasive tumour growth of melanoma cells in regenerated human skin. CONCLUSIONS: Combined targeting of MAPK and AKT signalling pathways is a promising strategy for melanoma treatment and should encourage further in-depth investigations.     

PI3K/Akt/mTOR信号通路在皮肤鳞状细胞癌中的研究进展

【摘要】 皮肤鳞状细胞癌的发病机制复杂，晚期治疗手段缺乏。本文综述磷脂酰肌醇3-激酶/蛋白激酶B/哺乳类动物雷帕霉素靶蛋白（PI3K/Akt/mTOR）信号通路在皮肤鳞状细胞癌发病机制中的作用及针对其的治疗进展，为皮肤鳞状细胞癌的靶向治疗提供新思路。     

ERK1/2 is highly phosphorylated in melanoma metastases and protects melanoma cells from cisplatin-mediated apoptosis

Activation (phosphorylation) of mitogen-activated protein kinase (MAPK) signal transduction through BRAF and RAS causes a variety of functional effects including cell survival and cell death. In this study, we observed high extracellular signal-regulated kinase (ERK)1/2 phosphorylation levels in clinical melanoma metastases and various melanoma cell lines. Treatment of melanoma cell lines with cisplatin, a potent antitumor agent, increased the level of phosphorylated-ERK (P-ERK)1/2 and enhanced chemoresistance through activation of the cell survival protein 90-kDa ribosomal S6 kinase (RSK)1. The mitogen-activated protein kinase kinase (MEK) inhibitor (U0126) was able to block this effect and reduced cell viability and sensitized cells to cisplatin-induced apoptosis, as shown by PARP cleavage, caspase 3 expression, and annexin-V staining. In conclusion, the MAP kinase-ERK pathway is activated in melanoma and reduces the sensitivity of melanoma to cisplatin. Thus, inhibition of ERK1/2 in combination with selected chemotherapeutic agents may hold promise for more effective therapy of melanoma.     

Immunohistochemical analysis of the mammalian target of rapamycin signalling pathway in extramammary Paget's disease

Background We have previously observed that persistent activation of the serine/threonine kinase, protein kinase B (AKT) is a frequent event in extramammary Paget’s disease (EMPD). AKT promotes cell proliferation by its ability to coordinate mitogenic signalling with energy‐ and nutrient‐sensing pathways that control protein synthesis through the atypical serine/threonine kinase, mammalian target of rapamycin (mTOR). CDK2, a member of the serine/threonine kinase family of cyclin‐dependent kinases, is a key regulator of G₁–S cell cycle progression, and has recently been shown to be one of the targets of AKT. The AKT–mTOR–p70 ribosomal protein S6 kinase (p70S6K) pathway has been described in some human malignancies, but not in EMPD. Objective To investigate the immunohistochemical staining of the AKT–mTOR–p70S6K pathway in EMPD and to evaluate the relationships among the components. Methods Samples of primary EMPD tissue were subjected to immunohistological staining with phosphorylated (p)‐AKT, p‐mTOR, p‐4E‐binding protein 1 (p‐4EBP1), p‐p70S6K/S6K1, p‐ribosomal protein S6 (p‐S6) and CDK2. Ten normal skin samples served as a control. Results Of the 32 EMPD tissue samples, 29, 27, 26, 29, 26 and 32 samples were positive for p‐AKT, p‐mTOR, p‐4EBP1, p‐p70S6K/S6K1, p‐S6 and CDK2 staining, respectively. All these cell signalling molecules showed higher positivity in invasive EMPD than in EMPD in situ. There were significant correlations between p‐AKT, p‐mTOR, p‐4EBP1, p‐p70S6K/S6K1 and p‐S6 and CDK2. Conclusions The activation of the AKT–mTOR–p70S6K pathway may play an important role in the pathogenesis of EMPD. The high expression of the components of the pathway was highly correlated with CDK2 expression, suggesting that the AKT/mTOR pathway may induce the malignant transition through CDK2 in EMPD. The AKT–mTOR–p70S6K pathway might be a potential therapeutic target in EMPD.