The RAS-regulated RAF-MEK1/2-ERK1/2 signalling pathway is de-regulated in a variety of cancers due to mutations in receptor tyrosine kinases (RTKs), negative regulators of RAS (such as NF1) and core pathway components themselves (RAS, BRAF, CRAF, MEK1 or MEK2). This has driven the development of a variety of pharmaceutical agents to inhibit RAF-MEK1/2-ERK1/2 signalling in cancer and both RAF and MEK inhibitors are now approved and used in the clinic. There is now much interest in targeting at the level of ERK1/2 for a variety of reasons. First, since the pathway is linear from RAF-to-MEK-to-ERK then ERK1/2 are validated as targets per se. Second, innate resistance to RAF or MEK inhibitors involves relief of negative feedback and pathway re-activation with all signalling going through ERK1/2, validating the use of ERK inhibitors with RAF or MEK inhibitors as an up-front combination. Third, long-term acquired resistance to RAF or MEK inhibitors involves a variety of mechanisms (KRAS or BRAF amplification, MEK mutation, etc.) which re-instate ERK activity, validating the use of ERK inhibitors to forestall acquired resistance to RAF or MEK inhibitors. The first potent highly selective ERK1/2 inhibitors have now been developed and are entering clinical trials. They have one of three discrete mechanisms of action – catalytic, “dual mechanism” or covalent – which could have profound consequences for how cells respond and adapt. In this review we describe the validation of ERK1/2 as anti-cancer drug targets, consider the mechanism of action of new ERK1/2 inhibitors and how this may impact on their efficacy, anticipate factors that will determine how tumour cells respond and adapt to ERK1/2 inhibitors and consider ERK1/2 inhibitor drug combinations.

RAS 调节的 RAF-MEK1/2-ERK1/2 信号通路在多种癌症中由于受体酪氨酸激酶 (RTK)、RAS 的负调节因子（如 NF1）和核心通路成分本身的突变而失调。 RAS、BRAF、CRAF、MEK1 或 MEK2）。这推动了多种药物的开发，以抑制癌症中的 RAF-MEK1/2-ERK1/2 信号传导，现在 RAF 和 MEK 抑制剂都已获批准并用于临床。由于各种原因，现在人们对靶向 ERK1/2 水平非常感兴趣。首先，由于从 RAF 到 MEK 到 ERK 的途径是线性的，因此 ERK1/2本身被验证为目标. 其次，对 RAF 或 MEK 抑制剂的先天抗性涉及减轻负反馈和通路重新激活，所有信号通过 ERK1/2，验证 ERK 抑制剂与 RAF 或 MEK 抑制剂作为前期组合的使用。第三，对 RAF 或 MEK 抑制剂的长期获得性耐药涉及恢复 ERK 活性的多种机制（KRAS 或 BRAF 扩增、MEK 突变等），验证了使用 ERK 抑制剂来预防对 RAF 或 MEK 的获得性耐药抑制剂。第一种强效高选择性 ERK1/2 抑制剂现已开发出来并进入临床试验阶段。它们具有三种不同的作用机制之一——催化、“双重机制”或共价——这可能对细胞的反应和适应产生深远的影响。