Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA.
Expert Rev Mol Med. 2012 Oct 12;14:e17. doi: 10.1017/erm.2012.11.
The mitogen-activated protein kinase (MAPK) pathway has been implicated in the pathophysiology of many cancers. Under normal physiologic conditions, the RAS-RAF-mitogen-activated protein kinase kinase (MEK)-mitogen-activated protein kinase (ERK) signalling cascade interaction is initiated by ligation of a receptor-linked tyrosine kinase by its cognate growth factor. It has been demonstrated in many systems that aberrant autocrine or paracrine stimulation of growth factor receptors is pathogenic in large part because of MAPK activation. As one of the key downstream effector pathways of mutated RAS (KRAS, NRAS and HRAS), pharmacologic inhibition of components of the MAPK pathway has been pursued as a means to indirectly inhibit RAS, which remains a technical challenge for direct pharmacologic inhibition. RAF and MEK are the two non-membrane-bound, serine-threonine and tyrosine-threonine kinases, within the pathway that have been most extensively explored as drug targets. The discovery of activating BRAF mutations in cancer clarified which cancer types and subsets of certain cancers are most dependent on activation of the MAPK pathway for growth and survival. Now, with the successful translation of selective BRAF and MEK inhibitors into validated therapies for BRAF mutant melanoma, the field seeks to resolve the role for these agents in cancers harbouring RAS mutations or those driven by aberrant growth factor receptor activation.
丝裂原活化蛋白激酶（MAPK）途径与许多癌症的病理生理学有关。在正常生理条件下，RAS-RAF-丝裂原活化蛋白激酶激酶（MEK）-丝裂原活化蛋白激酶（ERK）信号级联反应通过受体连接的酪氨酸激酶与其同源生长因子的结合而启动。在许多系统中已经证明，生长因子受体的异常自分泌或旁分泌刺激在很大程度上是致病性的，因为 MAPK 被激活。作为突变型 RAS（KRAS、NRAS 和 HRAS）的关键下游效应途径之一，MAPK 途径成分的药理学抑制已被作为间接抑制 RAS 的一种手段进行探索，而直接药理学抑制仍然是一个技术挑战。RAF 和 MEK 是该途径中两个非膜结合的丝氨酸-苏氨酸和酪氨酸-苏氨酸激酶，作为药物靶点已得到广泛研究。在癌症中发现激活的 BRAF 突变阐明了哪些癌症类型和某些癌症的亚组最依赖 MAPK 途径的激活来生长和存活。现在，随着选择性 BRAF 和 MEK 抑制剂成功转化为针对 BRAF 突变黑色素瘤的有效疗法，该领域试图确定这些药物在携带 RAS 突变或由异常生长因子受体激活驱动的癌症中的作用。
