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

KRAS突变肺腺癌是一种治疗困境，因为缺乏针对具有致癌KRAS突变的癌细胞的有效治疗选择。胸部放射治疗被用于许多肺腺癌，但关于如何使肺癌对辐射敏感的信息很少或根本没有，特别是在个别肿瘤癌基因型别的背景下。基于这个孢子项目的先前工作，我们有初步的数据，为使用人类和转基因小鼠临床前模型(KRAS突变的人原位移植肺腺癌模型和“KP”，Kras突变/TP53突变的小鼠，由于microRNA-200(miR-200)家族下调而患转移性肺腺癌)提供了一个基本的理论方法。根据这些数据， 我们假设并计划测试：(A)KRAS突变激活的下游信号通路和 MIR-200下调，即MAPK/ERK激酶(MEK1/2)和/或 磷脂酰肌醇3-激酶(PI3K)是KRAS突变肺耐受辐射的关键介质 (B)KRAS密码子12替换(G12D、G12V和G12C)和microRNA-200(miR- 家族表达水平预测肿瘤细胞对PI3K靶向治疗的敏感性。我们建议调查这些假设，具体目的如下： 具体目标1：用MEK1/2抑制剂曲美替尼和 研究曲美替尼获得性耐药的机制。 具体目标2：实施一项人类肺癌临床试验，检查曲美替尼是否 抑制MEK1/2使KRAS基因突变的肺腺癌对化疗和放射治疗敏感。 具体目标3：检查特定的KRAS密码子12替换和/或miR-200表达 在我们的临床前模型中，PI3K通路拮抗水平可以预测放射增敏作用。 这些研究发现作为放射增敏剂的MEK1/2和PI3K/mT0R抑制剂可能具有 对个性化肺癌临床护理产生立竿见影的影响，并为未来的临床试验奠定基础。 我们已经组建了一支由应用和基础研究人员组成的多学科团队，以确保这个项目的成功。

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.