Receptor tyrosine kinases and downstream pathways as druggable targets for cancer treatment: the current arsenal of inhibitors.
Receptor tyrosine kinases and downstream pathways as druggable targets for cancer treatment: the current arsenal of inhibitors.
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DOI：
10.1186/s12943-018-0792-2
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发表时间：
2018-02-19
期刊：
影响因子：
37.3
通讯作者：
Melo FHM
中科院分区：
文献类型：
--
作者：
Montor WR;Salas AROSE;Melo FHM
寻找允许在过度增殖状态（例如癌症）下药理学抑制细胞增殖的靶点，使我们能够精细地理解协调有丝分裂数量、频率和节奏的完美控制的复杂机制，以及诱导细胞进入功能性静止并使它们在特定条件下回到循环的分子排列。尽管调节细胞增殖的机制在几年前就已经被描述过，但在过去的十年中，当治疗靶点被探索并且分子（合成的或具有成为癌症药物的潜力的抗体形式的）被生产并针对特异性结合和功能进行调整时，从未有过如此多的光照射在这种机制上。含有酪氨酸激酶结构域的蛋白质，无论是膜受体还是细胞质分子，加上由下游途径中具有或不具有酪氨酸激酶结构域的那些激活的蛋白质，例如RAS（其是一种GTP酶）和丝氨酸/苏氨酸激酶（例如RAF），在将增殖信息从细胞周围传导到发生基因表达的细胞核中起关键作用。酪氨酸激酶以活化模式磷酸化酪氨酸残基，并且发现于重要的生长因子受体中，例如来自统称为VEGF、PDGF和EGF的家族的配体，仅举几例，以及细胞内下游分子中。它们都在正常生理学中发挥重要作用，并且通常在肿瘤状态中被发现突变或过表达。我们的目标是将这些激酶作为癌症治疗的药物靶点，突出药物库可用的激酶，讨论特异性，耐药机制和耐药情况下的治疗方案，并列出尚未成功工作的潜在靶点。
Searching for targets that allow pharmacological inhibition of cell proliferation in over-proliferative states, such as cancer, leads us to finely understand the complex mechanisms orchestrating the perfect control of mitosis number, frequency and pace as well as the molecular arrangements that induce cells to enter functional quiescence and brings them back to cycling in specific conditions. Although the mechanisms regulating cell proliferation have been described several years ago, never before has so much light been shed over this machinery as during the last decade when therapy targets have been explored and molecules, either synthetic or in the form of antibodies with the potential of becoming cancer drugs were produced and adjusted for specific binding and function. Proteins containing tyrosine kinase domains, either membrane receptors or cytoplasmic molecules, plus the ones activated by those in downstream pathways, having tyrosine kinase domains or not, such as RAS which is a GTPase and serine/threonine kinases such as RAF, play crucial role in conducting proliferation information from cell surroundings to the nucleus where gene expression takes place. Tyrosine kinases phosphorylate tyrosine residues in an activating mode and are found in important growth factor receptors, such as for ligands from families collectively known as VEGF, PDGF and EGF, to name a few and in intracellular downstream molecules. They all play important roles in normal physiology and are commonly found mutated or overexpressed in neoplastic states. Our objective here is to present such kinases as druggable targets for cancer therapy, highlighting the ones for which the pharmacological arsenal is available, discussing specificity, resistance mechanisms and treatment alternatives in cases of resistance, plus listing potential targets that have not been successfully worked yet.
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影响因子：
64.5
作者：
Cancer Genome Atlas Research Network
通讯作者：
Cancer Genome Atlas Research Network
影响因子：
28.2
作者：
Drilon A;Wang L;Hasanovic A;Suehara Y;Lipson D;Stephens P;Ross J;Miller V;Ginsberg M;Zakowski MF;Kris MG;Ladanyi M;Rizvi N
通讯作者：
Rizvi N
影响因子：
51.1
作者：
Ascierto, Paolo A.;Schadendorf, Dirk;Dummer, Reinhard
通讯作者：
Dummer, Reinhard
DOI：
10.1016/s0140-6736(12)61857-1
发表时间：
2013-01-26
期刊：
Lancet (London, England)
影响因子：
--
作者：
Demetri GD;Reichardt P;Kang YK;Blay JY;Rutkowski P;Gelderblom H;Hohenberger P;Leahy M;von Mehren M;Joensuu H;Badalamenti G;Blackstein M;Le Cesne A;Schöffski P;Maki RG;Bauer S;Nguyen BB;Xu J;Nishida T;Chung J;Kappeler C;Kuss I;Laurent D;Casali PG;GRID study investigators
通讯作者：
GRID study investigators
影响因子：
45.3
作者：
Adjei, AA;Mauer, A;Vokes, EE
通讯作者：
Vokes, EE