Preclinical Development and Clinical Testing of MEK and PI3K Targeted Therapy for KRAS-mutant NSCLC

KRAS突变型肺腺癌代表了一种治疗困境，因为缺乏特异性靶向具有致癌KRAS突变的癌细胞的有效治疗选择。胸部放射治疗用于许多肺腺癌，但很少或没有关于如何使肺癌对放射敏感的信息，特别是在个体肿瘤癌基因型的背景下。基于在该SPORE项目中的先前工作，我们具有初步数据，其使用人类和转基因小鼠临床前模型（KRAS突变的人类原位异种移植肺腺癌模型和“KP”，Kras突变/Tp 53突变小鼠，其由于microRNA-200（miR-200）家族的下调而发展转移性肺腺癌）提供了解决该重要问题的合理方法。根据这些数据， 我们假设并计划测试：（a）由KRAS突变激活的下游信号通路， miR-200下调，即由MAPK/ERK激酶（MEK 1/2）和/或 磷脂酰肌醇3-激酶（PI 3 K）是KRAS突变型肺辐射抗性的关键介质 腺癌;和（B）KRAS密码子12取代（G12 D、G12 V和G12 C）和微小RNA-200（miR-200）。 200)家族表达水平预测肿瘤细胞对PI 3 K靶向治疗剂的敏感性。我们建议调查这些假设，具体目标如下： 具体目标1：使用MEK 1/2抑制剂曲美替尼进行“小鼠-人联合临床试验”， 研究对曲美替尼获得性耐药的机制。 具体目标2：实施人肺癌临床试验，检查曲美替尼是否介导 抑制MEK 1/2可使KRAS突变型肺腺癌对放化疗敏感 具体目的3：检查是否存在特异性KRAS密码子12置换和/或miR-200表达 在我们的临床前模型中，PI 3 K水平通过PI 3 K通路拮抗作用预测放射增敏。 这些关于MEK 1/2和PI 3 K/mT 0 R抑制剂作为放射增敏剂的研究发现， 对个性化肺癌临床护理的直接影响，并为未来的临床试验奠定基础。 我们已经组建了一个多学科的应用和基础研究团队，以确保该项目的成功。

KRAS-mutant lung adenocarcinoma represents a therapeutic dilemma owing to a dearth of effective treatment options that specifically target cancer cells with oncogenic KRAS mutations. Thoracic radiation therapy is used in many lung adenocarcinomas but there is little or no information on how to sensitize lung cancers to radiation, particularly in the context of individual tumor oncogenotypes. Based on prior work in this SPORE Project we have preliminary data that provide a rationale approach to this important problem using both human and transgenic mouse preclinical models (KRAS-mutant human orthotopic xenograft lung adenocarcinoma model, and "KP", Kras-mutant/Tp53-mutant, mice, which develop metastatic lung adenocarcinomas owing to down-regulation of the microRNA-200 (miR-200) family). Based on these data, we hypothesize and plan to test that: (a) downstream signaling pathways activated by KRAS mutations and miR-200 down-regulation, namely those regulated by MAPK/ERK kinase (MEK1/2) and/or phosphatidylinositol 3-kinase (PI3K), are key mediators of radiation resistance in KRAS-mutant lung adenocarcinoma; and (b) KRAS codon 12 substitutions (G12D, G12V, and G12C) and microRNA-200 (miR- 200) family expression levels predict tumor cell sensitivity to PI3K targeted therapeutics. We propose to investigate these hypotheses with the following Specific Aims: Specific Aim 1: To carry out a "mouse-human co-clinical trial" with the MEK1/2 inhibitor Trametinib and examine mechanisms of acquired resistance to Trametinib. Specific Aim 2: To implement a human lung cancer clinical trial that examines whether Trametinib mediated MEK1/2 inhibition sensitizes KRAS-mutant lung adenocarcinomas to chemo-radiotherapy. Specific Aim 3: To examine whether specific KRAS codon 12 substitutions and/or miR-200 expression levels predict radiosensitization by PI3K pathway antagonism in our preclinical models. Findings from these studies on inhibitors of MEK1/2 and PI3K/mT0R as radiosensitizers can have immediate impact on personalizing lung cancer clinical care and lay the groundwork for future clinical trials. We have assembled a multidisciplinary team of applied and basic investigators fo ensure the success of this project.