INSERM, U976, Team 1, Human Immunology Pathophysiology & Immunotherapy (HIPI).
Université de Paris, Institut de Recherche Saint Louis (IRSL).
Curr Opin Oncol. 2021 Mar 1;33(2):120-126. doi: 10.1097/CCO.0000000000000708.
Although immune checkpoint inhibitors and small molecule inhibitors targeting the MAPK pathway have revolutionized the management of metastatic melanoma, long-term disease control occurs only for a minority of patients because of multiple resistance mechanisms. One way to tackle resistance is to develop the next-generation of RAF, MEK and ERK inhibitors using our understanding of the molecular mechanisms that fine-tune the MAPK pathway.
Studies on the regulation of the MAPK pathway have revealed a dominant role for homo-dimerization and hetero-dimerization of RAF, MEK and ERK. Allosteric inhibitors that break these dimers are, therefore, undergoing various stages of preclinical and clinical evaluation. Novel MEK inhibitors are less susceptible to differences in MEK's activation state and do not drive the compensatory activation of MEK that could limit efficacy. Innovations in targeting ERK originate from dual inhibitors that block MEK-catalyzed ERK phosphorylation, thereby limiting the extent of ERK reactivation following feedback relief.
The primary goal in RAF, MEK and ERK inhibitors' development is to produce molecules with less inhibitor paradox and off-target effects, giving robust and sustained MAPK pathway inhibition.
尽管针对 MAPK 通路的免疫检查点抑制剂和小分子抑制剂已经彻底改变了转移性黑色素瘤的治疗方法，但由于存在多种耐药机制，只有少数患者能够长期控制疾病。克服耐药性的一种方法是利用我们对精细调节 MAPK 通路的分子机制的理解，开发新一代 RAF、MEK 和 ERK 抑制剂。
对 MAPK 通路调控的研究揭示了 RAF、MEK 和 ERK 同源二聚体和异源二聚体的主导作用。因此，所有这些打破这些二聚体的别构抑制剂都正在进行不同阶段的临床前和临床评估。新型 MEK 抑制剂不太容易受到 MEK 激活状态差异的影响，并且不会驱动可能限制疗效的 MEK 代偿性激活。靶向 ERK 的创新源于双重抑制剂，它可以阻断 MEK 催化的 ERK 磷酸化，从而限制反馈缓解后 ERK 再激活的程度。
在 RAF、MEK 和 ERK 抑制剂的开发中，主要目标是产生具有更少的抑制剂悖论和脱靶效应的分子，从而实现稳健和持续的 MAPK 通路抑制。
