Targeting EphA2 in lung cancer subtypes that are refractory to current therapy

项目摘要/摘要 在美国，肺癌是与癌症相关的死亡的主要原因，而且对 退伍军人。在过去的十年中，非小细胞肺癌的进展导致了新的 具有最小毒性作用和显著临床益处的分子靶向治疗。然而， 尽管取得了这些进展，总体五年存活率仍保持在16%左右，部分原因是低 靶向治疗的应答率，获得性耐药性的发展，靶向的困难 蛋白质，如突变的K-RAS，以及具有未知基因改变的大亚群。因此， 对于目前难以获得的肺癌亚型，需要新的分子靶点 治疗。 EphA2是一个很有希望的目标。EphA2在非小细胞肺癌中高表达，高水平EphA2 与吸烟、脑转移、疾病复发和患者生存不良有关。一种收益- 在肿瘤标本中也发现了功能性EphA2突变，表明其具有致癌作用 EphA2在肺癌中的表达。事实上，我们发现EphA2的敲除在大量的 人类肺癌细胞系抑制了肿瘤细胞的活力，对那些携带 K-RAS突变或携带对酪氨酸激酶产生获得性耐药的EGFR突变 抑制剂(TKI)。为了支持这一观点，EphA2小分子激酶抑制剂抑制了细胞 K-ras基因突变人肺癌异种移植瘤的体外存活和诱导肿瘤消退。基座 根据这些初步数据，此次VA Merit续签的总体目标是确定 靶向EphA2在当前靶向治疗无效的肺癌亚型中的作用 EphA2在肿瘤中作用的分子基础，并检测小分子EphA2激酶抑制剂 癌症治疗学。 我们将首先研究EphA2缺乏对肺癌发生和发展的影响。 转基因K-RAS G12D和TKI耐药EGFR L858R+T790M肺癌模型体内研究进展至 阐明EphA2受体下游信号转导途径，我们将重点研究JNK/c-Jun通路在调控中的作用 肿瘤细胞活性和肿瘤干细胞样细胞功能。最后，我们将测试选择性小剂量的效果 EphA2受体的分子抑制剂。该项目的成功不仅将产生新的见解 EphA2 RTK调节肿瘤细胞活性的分子基础，也提供了新的EphA2- 用于治疗对当前靶向无效的肺癌亚型的选择性抑制剂 治疗，如K-RAS突变和耐药EGFR突变肺癌。

Project Summary/ Abstract Lung cancer is the leading cause of cancer-related deaths in the US and disproportionally affects Veterans. Advances in non-small-cell lung cancer over the past decade have resulted in new molecularly targeted therapies with minimal toxic effects and dramatic clinical benefits. However, despite these progresses, overall five-year survival remains at approximately 16%, partly due to low responsive rate to targeted therapy, development of acquired resistance, difficulty of targeting certain proteins such as mutant K-RAS, and a large subset with undefined genetic alterations. Therefore, new molecular targets are needed for lung cancer subtypes that are currently refractory to available treatments. EphA2 is such a promising target. EphA2 is overexpressed in NSCLC, and high levels of EphA2 correlate with smoking, brain metastasis, disease relapse, and poor patient survival. A gain-of- function EphA2 mutation has also been identified in tumor specimens, suggesting an oncogenic role of EphA2 in lung cancer. Indeed, we discovered that knockdown of EphA2 in a large numbers of human lung cancer cell lines inhibited tumor cell viability, most dramatically affecting those bearing mutant K-RAS or carrying EGFR mutation that developed acquired resistance to tyrosine kinase inhibitors (TKI). To support this notion, an EphA2 small molecule kinase inhibitor suppressed cell viability in vitro and induced tumor regression in K-RAS mutant human lung cancer xenografts. Based on these preliminary data, the overall goal of this VA Merit renewal is to determine the efficacy of targeting EphA2 in lung cancer subtypes that are refractory to current targeted treatment, to elucidate molecular basis for EphA2 function in tumor, and to test small molecule EphA2 kinase inhibitors for cancer therapeutics. We will first to investigate the effects of EphA2 deficiency on lung cancer development and progression in vivo in transgenic K-RAS G12D and TKI-resistant EGFR L858R+T790M lung cancer models. To elucidate EphA2 receptor downstream signaling, we will focus on the JNK/c-Jun pathway in regulating tumor cell viability and tumor stem-like cell function. Finally, we will test the efficacy of selective small molecule inhibitors of EphA2 receptor. Success of this project will not only generate novel insights into the molecular basis whereby EphA2 RTK regulates tumor cell viability, but also provide novel EphA2- selective inhibitors for treatment of lung cancer subtypes that are refractory to current targeted therapies, such as K-RAS mutant and drug-resistant EGFR mutant lung cancers.