Peptomyc S.L., Barcelona, Spain.
Models of cancer therapies Laboratory, Vall d'Hebron Institute of Oncology, Cellex Centre, Hospital University Vall d'Hebron Campus, Barcelona, Spain.
Signal Transduct Target Ther. 2024 Aug 21;9(1):205. doi: 10.1038/s41392-024-01907-z.
RAS and MYC rank amongst the most commonly altered oncogenes in cancer, with RAS being the most frequently mutated and MYC the most amplified. The cooperative interplay between RAS and MYC constitutes a complex and multifaceted phenomenon, profoundly influencing tumor development. Together and individually, these two oncogenes regulate most, if not all, hallmarks of cancer, including cell death escape, replicative immortality, tumor-associated angiogenesis, cell invasion and metastasis, metabolic adaptation, and immune evasion. Due to their frequent alteration and role in tumorigenesis, MYC and RAS emerge as highly appealing targets in cancer therapy. However, due to their complex nature, both oncogenes have been long considered "undruggable" and, until recently, no drugs directly targeting them had reached the clinic. This review aims to shed light on their complex partnership, with special attention to their active collaboration in fostering an immunosuppressive milieu and driving immunotherapeutic resistance in cancer. Within this review, we also present an update on the different inhibitors targeting RAS and MYC currently undergoing clinical trials, along with their clinical outcomes and the different combination strategies being explored to overcome drug resistance. This recent clinical development suggests a paradigm shift in the long-standing belief of RAS and MYC "undruggability", hinting at a new era in their therapeutic targeting.
RAS 和 MYC 是癌症中最常见的改变的癌基因之一，其中 RAS 突变最为频繁，而 MYC 扩增最为常见。RAS 和 MYC 之间的协同相互作用构成了一个复杂而多方面的现象，深刻影响着肿瘤的发展。这两个癌基因共同和单独调节着大多数（如果不是全部）癌症的标志性特征，包括细胞死亡逃逸、复制永生、肿瘤相关血管生成、细胞侵袭和转移、代谢适应和免疫逃逸。由于它们经常发生改变并在肿瘤发生中起作用，MYC 和 RAS 成为癌症治疗中极具吸引力的靶点。然而，由于它们的复杂性，这两个癌基因长期以来一直被认为是“不可成药的”，直到最近，没有任何直接针对它们的药物进入临床。本综述旨在阐明它们复杂的伙伴关系，特别关注它们在促进免疫抑制微环境和推动癌症免疫治疗耐药性方面的积极合作。在本综述中，我们还介绍了目前正在进行临床试验的针对 RAS 和 MYC 的不同抑制剂的最新情况，以及它们的临床结果和正在探索的克服耐药性的不同联合策略。这一最近的临床进展表明，人们对 RAS 和 MYC“不可成药”的长期信念发生了转变，暗示着它们的治疗靶向进入了一个新的时代。
