MYC and KRAS cooperation: from historical challenges to therapeutic opportunities in cancer.

IF 40.8 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Signal Transduction and Targeted Therapy Pub Date : 2024-08-21 DOI:10.1038/s41392-024-01907-z
Sílvia Casacuberta-Serra, Íñigo González-Larreategui, Daniel Capitán-Leo, Laura Soucek
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Abstract

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.

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MYC 和 KRAS 的合作:从历史挑战到癌症治疗机遇。
RAS 和 MYC 是癌症中最常发生变化的癌基因之一,其中 RAS 最常发生突变,而 MYC 则最常发生扩增。RAS 和 MYC 之间的合作性相互作用构成了一个复杂而多面的现象,对肿瘤的发展产生了深远的影响。这两个癌基因共同或单独调控着癌症的大多数(如果不是全部)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、代谢适应和免疫逃避。由于 MYC 和 RAS 在肿瘤发生中的频繁变化和作用,它们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,这两种癌基因长期以来一直被认为是 "不可药用 "的,直到最近,还没有直接针对它们的药物进入临床。本综述旨在阐明它们之间复杂的合作关系,特别关注它们在促进免疫抑制环境和驱动癌症免疫治疗抗药性方面的积极合作。在这篇综述中,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组合策略。最近的临床发展表明,长期以来认为 RAS 和 MYC "不可药用 "的观点发生了范式转变,预示着它们的靶向治疗进入了一个新时代。
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来源期刊
Signal Transduction and Targeted Therapy
Signal Transduction and Targeted Therapy Biochemistry, Genetics and Molecular Biology-Genetics
CiteScore
44.50
自引率
1.50%
发文量
384
审稿时长
5 weeks
期刊介绍: Signal Transduction and Targeted Therapy is an open access journal that focuses on timely publication of cutting-edge discoveries and advancements in basic science and clinical research related to signal transduction and targeted therapy. Scope: The journal covers research on major human diseases, including, but not limited to: Cancer,Cardiovascular diseases,Autoimmune diseases,Nervous system diseases.
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