Molecular Pharmacology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCSS Istituto Nazionale dei Tumori, via Amadeo 42, 20133 Milan, Italy.
Curr Pharm Des. 2013;19(5):883-94.
Mitogen-activated protein kinases (MAPK) are involved in a complex network which regulates a variety of cellular processes including proliferation, survival and death. The molecular characterization of the pathway has shown aberrant activation in several human tumors, due to the deregulation of receptor tyrosine kinases or to mutations of pathway components. Progress in understanding the MAPK network has led to the development of target-specific agents in clinical trials. The relevance of MAPK in response and resistance to antitumor agents has been recognized, although the outcome of MAPK activation can vary depending on the molecular background of tumor cells and on the type of activated kinase. The canonical cascade of MAPK, i.e., depending on the Extracellular Signal-Regulated Kinases (ERK), can act in protective signalling pathways, thereby limiting DNA damage. Since tumor cell survival can be sustained by ERK and cross talk of ERK with other pathways, modulation of sensitivity to antitumor agents by targeting the ERK cascade appears to be an amenable approach. Indeed, ERK play a role in resistance to both cytotoxic and target-specific agents. Preclinical studies support the relevance of drug combination approaches to enhance the efficacy of antitumor treatments. Combinations of pharmacological inhibitors of the ERK cascade and conventional or target-specific antitumor agents may be helpful in an attempt to overcome drug resistance. A deeper understanding of the genetic alterations of tumor cells and of tumor heterogeneity as well as of drug resistance mechanisms is expected to contribute to the rational design of MAPK-mediated drug combinations that will lead to reversal of drug resistance.
丝裂原活化蛋白激酶（MAPK）参与了一个复杂的网络，调节着包括增殖、存活和死亡在内的多种细胞过程。该通路的分子特征显示，由于受体酪氨酸激酶的失调或通路成分的突变，在几种人类肿瘤中存在异常激活。对 MAPK 网络的理解进展导致了临床试验中靶向特异性药物的开发。已经认识到 MAPK 在对抗肿瘤药物的反应和耐药性中的相关性，尽管 MAPK 的激活结果可能因肿瘤细胞的分子背景和激活激酶的类型而异。MAPK 的经典级联，即依赖细胞外信号调节激酶（ERK），可以在保护性信号通路中发挥作用，从而限制 DNA 损伤。由于 ERK 可以维持肿瘤细胞的存活，并且 ERK 与其他通路的相互作用，因此靶向 ERK 级联来调节对肿瘤药物的敏感性似乎是一种可行的方法。事实上，ERK 在细胞毒性药物和靶向药物的耐药性中都发挥作用。临床前研究支持药物联合应用方法来提高抗肿瘤治疗的疗效。ERK 级联的药理学抑制剂与常规或靶向抗肿瘤药物的联合应用可能有助于克服耐药性。对肿瘤细胞遗传改变和肿瘤异质性以及耐药机制的深入了解，有望有助于合理设计 MAPK 介导的药物联合治疗，从而逆转耐药性。
