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.

尽管 RAS 以前被认为是不可成药的，但现在已经开发出了各种抑制 RAS 或特定 RAS 癌蛋白的药物。事实上，最近突变选择性 KRAS 抑制剂的临床成功证明了直接靶向 RAS 的重要性。然而，对这些药物的反应通常是不完整的，并且仅限于一部分患者，这突出表明需要开发更有效的治疗方法，这可能需要组合方法。针对 RAS 通路内多个节点以实现更深层次抑制的垂直策略正在研究中，并且在其他情况下具有优先权。然而，已经确定了共同针对 RAS 和其他治疗漏洞的替代策略，这可能会减轻对深度通路抑制的需求。无论如何，任何给定方法的功效都可能取决于遗传、表观遗传和肿瘤特异性变量。在这里，我们讨论了治疗 KRAS 驱动的癌症的各种组合策略，强调了可能扩展到含有其他 RAS 突变的肿瘤的机制概念。尽管已经确定了许多有希望的组合，但临床反应最终将取决于是否可以实现治疗窗口以及我们前瞻性地选择有反应的患者的能力。因此，我们必须继续开发和了解生物多样性策略，以最大限度地提高成功的可能性。