CDK4/6 和 MEK 抑制相结合作为一种治疗策略已在各种癌症模型中显示出前景，特别是在那些含有 RAS 突变的癌症模型中。初步的高通量药物筛选发现，CDK4/6 抑制剂 palbociclib 和 MEK 抑制剂曲美替尼 (trametinib) 联合用于软组织肉瘤时具有高度协同作用。在 RAS 突变模型中，palbociclib 和曲美替尼联合治疗可诱导显着的 G1 细胞周期停滞，导致细胞增殖和生长显着减少。 CRISPR 介导的 RB1 耗竭导致对 CDK4/6 和 MEK 抑制的反应减弱，这一点在细胞培养和异种移植模型中得到了验证。除了细胞周期抑制作用之外，通路富集分析还揭示了干扰素通路在 CDK4/6 和 MEK 抑制后的强烈激活。这种基因表达的诱导与逆转录病毒元件的上调有关。 TBK1（TANK 结合激酶 1）抑制剂 GSK8612 选择性阻断 palbociclib 和曲美替尼治疗诱导的干扰素相关基因的诱导，并突出了 CDK4/6 和 MEK 联合抑制引起的可分离的表观遗传反应。总之，这些发现为 CDK4/6 和 MEK 抑制在软组织肉瘤中的治疗潜力提供了关键的机制见解。

The combination of CDK4/6 and MEK inhibition as a therapeutic strategy has shown promise in various cancer models, particularly in those harboring RAS mutations. An initial high-throughput drug screen identified a high synergy between the CDK4/6 inhibitor palbociclib and the MEK inhibitor trametinib when used in combination in soft tissue sarcomas. In RAS mutant models, combination treatment with palbociclib and trametinib induced significant G1 cell cycle arrest, resulting in a marked reduction in cell proliferation and growth. CRISPR-mediated RB1 depletion resulted in a decreased response to CDK4/6 and MEK inhibition, which was validated in both cell culture and xenograft models. Beyond its cell cycle inhibitory effects, pathway enrichment analysis revealed the robust activation of interferon pathways upon CDK4/6 and MEK inhibition. This induction of gene expression was associated with the upregulation of retroviral elements. The TBK1(TANK-binding kinase 1) inhibitor GSK8612 selectively blocked the induction of interferon-related genes induced by palbociclib and trametinib treatment, and highlighted the separable epigenetic responses elicited by combined CDK4/6 and MEK inhibition. Together, these findings provide key mechanistic insights into the therapeutic potential of CDK4/6 and MEK inhibition in soft tissue sarcoma.