Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Cancer Res. 2022 Sep 16;82(18):3335-3344. doi: 10.1158/0008-5472.CAN-22-0198.
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.
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.
KRAS 和 NRAS 突变发生在 45%的结直肠癌中，联合 MAPK 通路和 CDK4/6 抑制被确定为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衍生的异种移植（PDX）的合作临床试验中进行了评估，并在具有 RAS 突变的转移性结直肠癌患者的 binimetinib 和 palbociclib 临床试验中建立了安全性。在接受 MEK 和 CDK4/6 双重抑制的 18 个 PDX 模型中，有 60%的肿瘤消退，达到了合作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 的临床评估在安全先导中确认了安全性，并提供了初步的活性证据。PDX 模型中的延长治疗导致受体酪氨酸激酶的反馈激活和获得性耐药，这可以用 SHP2 抑制剂逆转。这些结果突出了该组合在结直肠癌中的临床潜力，以及基于 PDX 的合作临床试验平台在药物开发中的实用性。
这项联合 MEK-CDK4/6 抑制治疗 RAS 突变结直肠癌的合作临床试验在患者衍生的异种移植中证明了治疗效果，在患者中证明了安全性，确定了反应的生物标志物，并揭示了可靶向的耐药机制。
