Targeting the mitogen-activated protein kinase pathway in the treatment of malignant melanoma
Targeting the mitogen-activated protein kinase pathway in the treatment of malignant melanoma
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DOI：
10.1158/1078-0432.ccr-05-2539
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发表时间：
2006-04-01
影响因子：
11.5
通讯作者：
Mier, JW
中科院分区：
文献类型：
--
作者：
Panka, DJ;Atkins, MB;Mier, JW
丝裂原活化蛋白激酶（MAPK;即，Ras-Raf-Erk）途径是黑色素瘤中治疗性干预的有吸引力的靶标，这是由于其在调节增殖、侵袭性和存活中的不可或缺的作用以及最近可获得的抑制构成该途径的各种激酶和GTP酶的药剂。遗传学研究已经确定了在大多数皮肤黑色素瘤中B-raf或N-ras的激活突变。其他研究已经描述了自分泌生长因子的作用（例如，肝细胞生长因子和成纤维细胞生长因子）对黑色素瘤中MAPK活化的影响。尽管如此，其他人强调了内源性raf抑制剂下调的后果，如Sprouty家族成员（例如，SPRY 2）和raf-1激酶抑制蛋白，在该通路的调节中起作用。黑色素瘤细胞用于确保MAPK通路活性的分子机制的多样性证明了其在疾病演变中的重要性以及该通路抑制剂可能被证明在黑色素瘤治疗中高度有效的可能性。MAPK抑制已显示导致促凋亡Bcl-2家族成员Bad和Bim的去磷酸化。这个过程反过来导致半胱天冬酶激活，并最终通过诱导细胞凋亡导致黑色素瘤细胞死亡。最近的几项研究已经确定了非丝裂原活化蛋白/细胞外信号调节激酶激酶结合伙伴的raf，并建议通过这些替代目标介导的raf和raf抑制的致死性的促生存作用，独立的MAPK途径。其他研究表明，内皮细胞是raf抑制剂在体内的主要靶点，这些药物的抗肿瘤作用主要归因于血管生成抑制。本文综述了黑色素瘤中MAPK激活的遗传和生化因素，抑制该途径可能对肿瘤细胞有害的机制，以及MAPK抑制剂在治疗该疾病中的潜力。
The mitogen-activated protein kinase (MAPK; i.e., Ras-Raf-Erk) pathway is an attractive target for therapeutic intervention in melanoma due to its integral role in the regulation of proliferation, invasiveness, and survival and the recent availability of pharmaceutical agents that inhibit the various kinases and GTPases that comprise the pathway. Genetic studies have identified activating mutations in either B-raf or N-ras in most cutaneous melanomas. Other studies have delineated the contribution of autocrine growth factors (e.g., hepatocyte growth factor and fibroblast growth factor) to MAPK activation in melanoma. Still, others have emphasized the consequences of the down-modulation of endogenous raf inhibitors, such as Sprouty family members (e.g., SPRY2) and raf-1 kinase inhibitory protein, in the regulation of the pathway. The diversity of molecular mechanisms used by melanoma cells to ensure the activity of the MAPK pathway attests to its importance in the evolution of the disease and the likelihood that inhibitors of the pathway may prove to be highly effective in melanoma treatment. MAPK inhibition has been shown to result in the dephosphorylation of the proapoptotic Bcl-2 family members Bad and Bim. This process in turn leads to caspase activation and, ultimately, the demise of melanoma cells through the induction of apoptosis. Several recent studies have identified non-mitogen-activated protein/extracellular signal-regulated kinase kinase-binding partners of raf and suggested that the prosurvival effects of raf and the lethality of raf inhibition are mediated through these alternative targets, independent of the MAPK pathway. Other studies have suggested that endothelial cells are the primary targets of raf inhibitors in vivo and that the antitumor effect of these agents are largely attributable to angiogenesis inhibition. This article reviews the genetic and biochemical factors contributing to MAPK activation in melanoma, the mechanisms by which inhibition of the pathway might prove deleterious to tumor cells, and the potential of MAPK inhibitors in the treatment of the disease.