A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response

摘要

Targeted therapies have demonstrated efficacy against specific subsets of molecularly defined cancers. Although most patients with lung cancer are stratified according to a single oncogenic driver, cancers harbouring identical activating genetic mutations show large variations in their responses to the same targeted therapy. The biology underlying this heterogeneity is not well understood, and the impact of co-existing genetic mutations, especially the loss of tumour suppressors, has not been fully explored. Here we use genetically engineered mouse models to conduct a 'co-clinical' trial that mirrors an ongoing human clinical trial in patients with KRAS-mutant lung cancers. This trial aims to determine if the MEK inhibitor selumetinib (AZD6244) increases the efficacy of docetaxel, a standard of care chemotherapy. Our studies demonstrate that concomitant loss of either p53 (also known as Tp53) or Lkb1 (also known as Stk11), two clinically relevant tumour suppressors, markedly impaired the response of Kras-mutant cancers to docetaxel monotherapy. We observed that the addition of selumetinib provided substantial benefit for mice with lung cancer caused by Kras and Kras and p53 mutations, but mice with Kras and Lkbl mutations had primary resistance to this combination therapy. Pharmacodynamic studies, including positron-emission tomography (PET) and computed tomography (CT), identified biological markers in mice and patients that provide a rationale for the differential efficacy of these therapies in the different genotypes. These co-clinical results identify predictive genetic biomarkers that should be validated by interrogating samples from patients enrolled on the concurrent clinical trial. These studies also highlight the rationale for synchronous co-clinical trials, not only to anticipate the results of ongoing human clinical trials, but also to generate clinically relevant hypotheses that can inform the analysis and design of human studies.%“共临床”（co-clinical）试验的思想是作为评估新疗法的方法提出的。这种想法是，通过在人类临床试验和小鼠临床前试验中同时测试一种药物，可以将两组数据合在一起，来提取额外的信息。为了演示这种方法的潜力，用基因工程方法培育的小鼠模型，被用来模仿用化疗药物“Docetaxel”治疗由KRAS驱动的肝癌的随机化的二期临床试验，并将单独使用该药物的作用与将其和一种MEK抑制药物组合使用的作用进行比较。在该小鼠模型中，带Kras或Kras和p53突变的肿瘤，对于组合用药的反应要比对单独作用“Docetaxel”的反应更大，而除了携带一个Lkb1被删除的突变以外还有被激发的Kras的小鼠相对来说没有反应。这一发现对目前正在进行当中的临床试验有重要意义，说明应对患者进行有关LKB1突变的测试。