The RAS–ERK pathway plays a major regulatory role in various cellular processes. This pathway is hyperactivated and takes an active part in the malignant transformation of more than 85% of cancers. The hyperactivation is mainly due to oncogenic activating mutations in the pathway's components RAS, RAF and MEK, but also due to indirect mechanisms in cells transformed by other oncogenes. Various inhibitors targeting the different tiers of the cascade have been successfully developed and clinically approved, while some are still undergoing preclinical and clinical evaluation. Treatments with the clinically approved RAF and MEK inhibitors have substantially improved the clinical outcome of metastatic mutated-BRAF melanoma. However, the rapid emergence of drug resistance of initially responsive cancers and limited efficacy towards other cancers has led to only marginal patient benefit. Deciphering the molecular mechanisms underlying intrinsic or acquired resistance is a necessity in order to enhance the treatment efficacy of ERK-addicted cancers. Therefore, many studies in the past 5 years embarked on this campaign, revealing several resistance mechanisms. These include, expression of drug-resistant RAF isoforms, molecular or genetic alterations of active downstream components, overexpression of upstream components of the cascade that can reactivate ERK and other survival-related pathways. The understanding of these molecular resistance mechanisms led to further development of drugs that can overcome drug resistance, including our own effort aiming to prevent the nuclear translocation of ERK without affecting its activation. In this review we will focus on the mechanisms underlying drug resistance and efforts to develop activity-independent, more efficacious, antitumor drugs.

RAS-ERK途径在各种细胞过程中起着重要的调节作用。该途径是高度活化的，并且在超过85％的癌症的恶性转化中起作用。过度激活主要是由于该途径的成分RAS，RAF和MEK中的致癌性激活突变，也归因于其他致癌基因转化的细胞中的间接机制。已经成功开发出了针对级联反应的不同层次的各种抑制剂，并在临床上得到了批准，而一些抑制剂仍在进行临床前和临床评估。临床批准的RAF和MEK抑制剂的治疗已大大改善了转移性突变BRAF黑色素瘤的临床疗效。然而，最初反应迅速的癌症的耐药性迅速出现，以及对其他癌症的疗效有限，仅给患者带来了微不足道的收益。为了增强ERK上瘾的癌症的治疗功效，有必要阐明内在或获得性抗性的分子机制。因此，在过去的5年中，许多研究开始了这项运动，揭示了几种抵抗机制。这些包括耐药性RAF同工型的表达，活性下游成分的分子或遗传改变，级联反应上游成分的过表达，这些成分可以重新激活ERK和其他与生存相关的途径。对这些分子耐药机制的理解导致了可以克服耐药性的药物的进一步开发，包括我们自己的努力，目的是在不影响ERK活化的情况下防止ERK的核易位。在这篇综述中，我们将重点研究耐药性的潜在机制以及开发与活性无关，更有效的抗肿瘤药物的努力。