KRAS and NRAS mutations occur in 45% of colorectal cancers, with combined MAPK pathway and CDK4/6 inhibition identified as a potential therapeutic strategy. In the current study, this combinatorial treatment approach was evaluated in a co-clinical trial in patient-derived xenografts (PDX), and safety was established in a clinical trial of binimetinib and palbociclib in patients with metastatic colorectal cancer with RAS mutations. Across 18 PDX models undergoing dual inhibition of MEK and CDK4/6, 60% of tumors regressed, meeting the co-clinical trial primary endpoint. Prolonged duration of response occurred predominantly in TP53 wild-type models. Clinical evaluation of binimetinib and palbociclib in a safety lead-in confirmed safety and provided preliminary evidence of activity. Prolonged treatment in PDX models resulted in feedback activation of receptor tyrosine kinases and acquired resistance, which was reversed with a SHP2 inhibitor. These results highlight the clinical potential of this combination in colorectal cancer, along with the utility of PDX-based co-clinical trial platforms for drug development. Significance: This co-clinical trial of combined MEK-CDK4/6 inhibition in RAS mutant colorectal cancer demonstrates therapeutic efficacy in patient-derived xenografts and safety in patients, identifies biomarkers of response, and uncovers targetable mechanisms of resistance.

中文翻译：

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通过 MEK 和 CDK4/6 双重抑制作用靶向 RAS 突变结直肠癌

KRAS 和 NRAS 突变发生在 45% 的结直肠癌中，MAPK 通路和 CDK4/6 抑制相结合被认为是一种潜在的治疗策略。在当前的研究中，这种组合治疗方法在患者来源的异种移植物 (PDX) 的联合临床试验中进行了评估，并在患有 RAS 突变的转移性结直肠癌患者中进行的 binimetinib 和 palbociclib 的临床试验中确定了安全性。在接受 MEK 和 CDK4/6 双重抑制的 18 个 PDX 模型中，60% 的肿瘤消退，达到了联合临床试验的主要终点。反应持续时间延长主要发生在 TP53 野生型模型中。Binimetinib 和 Palbociclib 在安全性导入中的临床评估证实了安全性并提供了初步的活性证据。PDX 模型中的长期治疗导致受体酪氨酸激酶的反馈激活和获得性耐药，而 SHP2 抑制剂可以逆转这种情况。这些结果凸显了该组合在结直肠癌中的临床潜力，以及基于 PDX 的药物开发联合临床试验平台的实用性。意义：这项联合 MEK-CDK4/6 抑制治疗 RAS 突变结直肠癌的联合临床试验证明了患者来源的异种移植物的治疗效果和患者的安全性，确定了反应的生物标志物，并揭示了靶向耐药机制。