尽管大约一半的转移性结直肠癌（mCRCs）携带KRAS或NRAS基因突变，但在过去几年中在针对此群体的靶向治疗方面几乎没有取得任何进展。因此，本研究通过靶向表皮生长因子受体（EGFR）和丝裂原活化蛋白激酶激酶（MEK）抑制RAS途径的垂直作用，对携带初级KRAS突变的患者来源的异种移植瘤（PDX）瘤进行了疗效研究。总共检测了19个不同的PDX模型，共127个瘤。根据基线肿瘤的变化进行了反应评估，分别为部分反应（PR; ≤-30%），稳定疾病（SD; -30%到+20%之间）或进行性疾病（PD; ≥+20%）。使用trametinib和cetuximab进行垂直抑制，在74%的分析模型中诱导了SD或PR，而单药trametinib只有24%的反应。在垂直抑制的PR病例中（47%），反应持久（长至137天），并且发生二级抵抗的发生率较低。分子分析显示，在相当一部分肿瘤中，初级和二级抵抗是由转录重编程激活RAS途径引起的。综上所述，这些临床前数据强烈支持该联合治疗方案进入结直肠癌患者的临床试验。本文受版权保护。版权所有。

Although approximately half of all metastatic colorectal cancers (mCRCs) harbor mutations in KRAS or NRAS, hardly any progress has been made regarding targeted treatment for this group over the last few years. Here, we investigated the efficacy of vertical inhibition of the RAS-pathway by targeting epidermal growth factor receptor (EGFR) and mitogen-activated protein kinase kinase (MEK) in patient-derived xenograft (PDX) tumors with primary KRAS mutation. In total, 19 different PDX models comprising 127 tumors were tested. Responses were evaluated according to baseline tumor changes and graded as partial response (PR; ≤-30%), stable disease (SD; between -30% and +20%) or progressive disease (PD; ≥+20%). Vertical inhibition with trametinib and cetuximab induced SD or PR in 74% of analyzed models, compared to 24% by monotherapy with trametinib. In cases of PR by vertical inhibition (47%), responses were lasting (as long as day 137), with a low incidence of secondary resistance. Molecular analyses revealed that primary and secondary resistance was driven by transcriptional reprogramming activating the RAS pathway in a substantial fraction of tumors. Together, these preclinical data strongly support the translation of this combination therapy into clinical trials for CRC patients.This article is protected by copyright. All rights reserved.