Targeting RAS Mutant Colorectal Cancer with Dual Inhibition of MEK and CDK4/6.
Targeting RAS Mutant Colorectal Cancer with Dual Inhibition of MEK and CDK4/6.
复制标题
双重抑制MEK和CDK4/6靶向RAS突变型结直肠癌
DOI：
10.1158/0008-5472.can-22-0198
复制
发表时间：
2022-09-16
期刊：
影响因子：
11.2
通讯作者：
中科院分区：
文献类型：
--
作者：
这项联合应用MEK-CDK4/6抑制RAS基因突变的结直肠癌的联合临床试验证明了在患者来源的异种移植中的治疗效果和患者的安全性，确定了反应的生物标记物，并揭示了靶向耐药机制。KRAS和NRAS突变发生在45%的结直肠癌中，MAPK通路和CDK4/6联合抑制被认为是一种潜在的治疗策略。在目前的研究中，这种联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，并在具有RAS突变的转移性结直肠癌患者的临床试验中确定了比尼美替尼和帕博西利的安全性。在接受MEK和CDK4/6双重抑制的18个PDX模型中，60%的肿瘤消退，满足共同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。临床评价比尼美替尼和帕波西利在安全导入中证实了安全性，并提供了活性的初步证据。在PDX模型中，长期治疗导致受体酪氨酸激酶的反馈激活和获得性耐药，这一点可被SHP2抑制剂逆转。这些结果突出了这种组合在结直肠癌中的临床潜力，以及基于PDX的联合临床试验平台在药物开发中的效用。这项联合应用MEK-CDK4/6抑制RAS基因突变的结直肠癌的联合临床试验证明了在患者来源的异种移植中的治疗效果和患者的安全性，确定了反应的生物标记物，并揭示了靶向耐药机制。
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 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.