RAS mutations occur in approximately 30% of tumors worldwide and have a poor prognosis due to limited therapies. Covalent targeting of KRAS G12C has achieved significant success in recent years, but there is still a lack of efficient therapeutic approaches for tumors with non-G12C KRAS mutations. A highly promising approach is to target the MAPK pathway downstream of RAS, with a particular focus on RAF kinases. First-generation RAF inhibitors have been authorized to treat BRAF mutant tumors for over a decade. However, their use in RAS-mutated tumors is not recommended due to the paradoxical ERK activation mainly caused by RAF dimerization. To address the issue of RAF dimerization, type II RAF inhibitors have emerged as leading candidates. Recent clinical studies have shown the initial effectiveness of these agents against RAS mutant tumors. Promisingly, type II RAF inhibitors in combination with MEK or ERK inhibitors have demonstrated impressive efficacy in RAS mutant tumors. This review aims to clarify the importance of RAF dimerization in cellular signaling and resistance to treatment in tumors with RAS mutations, as well as recent progress in therapeutic approaches to address the problem of RAF dimerization in RAS mutant tumors.

中文翻译：

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靶向 RAS 突变肿瘤中的 RAF 二聚体：从生物学到临床

RAS 突变发生在全球约 30% 的肿瘤中，并且由于治疗有限，预后较差。KRAS G12C 共价靶向近年来取得了巨大成功，但针对非 G12C KRAS 突变的肿瘤仍缺乏有效的治疗方法。一种非常有前途的方法是针对 RAS 下游的 MAPK 通路，特别关注 RAF 激酶。第一代 RAF 抑制剂已被授权治疗 BRAF 突变肿瘤十多年。然而，由于主要由 RAF 二聚化引起的矛盾的 ERK 激活，不建议将它们用于 RAS 突变的肿瘤。为了解决 RAF 二聚化问题，II 型 RAF 抑制剂已成为主要候选药物。最近的临床研究表明这些药物对 RAS 突变肿瘤具有初步疗效。令人鼓舞的是，II 型 RAF 抑制剂与 MEK 或 ERK 抑制剂联合治疗 RAS 突变肿瘤已显示出令人印象深刻的疗效。本综述旨在阐明 RAF 二聚化在细胞信号传导和 RAS 突变肿瘤治疗耐药中的重要性，以及解决 RAS 突变肿瘤中 RAF 二聚化问题的治疗方法的最新进展。