文章：

针对RAS驱动癌症的组合策略

Combinatorial strategies to target RAS-driven cancers

原文发布日期：2024-04-16

DOI: 10.1038/s41568-024-00679-6

类型: Review Article

开放获取: 否

英文摘要：

Although RAS was formerly considered undruggable, various agents that inhibit RAS or specific RAS oncoproteins have now been developed. Indeed, the importance of directly targeting RAS has recently been illustrated by the clinical success of mutant-selective KRAS inhibitors. Nevertheless, responses to these agents are typically incomplete and restricted to a subset of patients, highlighting the need to develop more effective treatments, which will likely require a combinatorial approach. Vertical strategies that target multiple nodes within the RAS pathway to achieve deeper suppression are being investigated and have precedence in other contexts. However, alternative strategies that co-target RAS and other therapeutic vulnerabilities have been identified, which may mitigate the requirement for profound pathway suppression. Regardless, the efficacy of any given approach will likely be dictated by genetic, epigenetic and tumour-specific variables. Here we discuss various combinatorial strategies to treat KRAS-driven cancers, highlighting mechanistic concepts that may extend to tumours harbouring other RAS mutations. Although many promising combinations have been identified, clinical responses will ultimately depend on whether a therapeutic window can be achieved and our ability to prospectively select responsive patients. Therefore, we must continue to develop and understand biologically diverse strategies to maximize our likelihood of success.

摘要翻译： 

尽管RAS曾被认为不可成药，但目前已经开发出多种抑制RAS或特定RAS癌蛋白的制剂。事实上，突变选择性KRAS抑制剂的临床成功最近直接证明了靶向RAS的重要性。然而，对这些药物的反应通常不完全且仅限于部分患者，这凸显了开发更有效治疗方法的必要性，而这很可能需要联合治疗策略。目前正在研究针对RAS通路内多个节点的垂直策略以实现更深度的抑制，这在其他背景下已有先例。不过，研究人员也发现了联合靶向RAS与其他治疗脆弱点的替代策略，或可减轻对深度通路抑制的需求。无论如何，任何特定方法的疗效很可能取决于遗传、表观遗传和肿瘤特异性变量。本文讨论了治疗KRAS驱动型癌症的各种联合策略，重点阐述了可能适用于其他RAS突变肿瘤的机制概念。虽然已确定许多有前景的联合方案，但临床反应最终取决于能否获得治疗窗口以及我们前瞻性筛选应答患者的能力。因此，我们必须继续开发和理解生物学多样化的策略，以最大限度地提高成功可能性。

原文链接：

Combinatorial strategies to target RAS-driven cancers