Antitumor Mechanisms of SRC Inhibitors in Lung Cancer

描述（由申请人提供）：SRC蛋白可将受体酪氨酸激酶连接至关键下游致癌途径，如PI 3 K/PTEN/Akt、STAT和Ras/Raf/ERK。这些关键通路的调节允许SRC控制细胞生长和增殖、存活、侵袭和血管生成。基于EGFR信号在肺癌中的重要性以及EGFR和SRC蛋白之间已知的合作，我们评估了新型SRC抑制剂在具有确定EGFR状态的肺癌细胞系中的有效性。SRC抑制通过诱导细胞凋亡降低突变型EGFR肺癌细胞活力，而对野生型EGFR的细胞系没有显著的细胞凋亡作用。EGFR突变细胞系中凋亡的诱导对应于激活的Akt和StatS存活蛋白的下调。在没有EGFR突变的细胞系中，SRC抑制降低了细胞周期蛋白D并增加了p27蛋白水平，并相应地导致G1细胞周期停滞。SRC抑制还抑制活化的FAK并抑制肺癌细胞侵袭。这些数据表明，新型SRC抑制剂可能是肺癌患者的有效疗法，特别是那些由突变EGFR蛋白驱动的患者。这项研究计划的目的是进一步表征新型SRC激酶抑制剂在肺癌细胞中的作用。在具体目标1中，我们将表征SRC抑制剂对具有确定EGFR状态的肺癌细胞中的细胞凋亡和生长抑制的作用。我们将评估对控制细胞凋亡和细胞生长的关键下游途径如PI 3 K/PTEN/Akt和STAT的影响。我们将评估EGFR和SRC酪氨酸激酶抑制剂组合对细胞凋亡和生长抑制的作用。在具体目标2中，我们将用相应的生物标志物分析评估SRC抑制对肺癌异种移植模型中体内肿瘤生长的影响。我们计划检验这一假设，即SRC抑制剂治疗EGFR突变的肺癌异种移植物将通过增强细胞凋亡而经历肿瘤消退，而野生型EGFR异种移植物的治疗将导致生长抑制。上述目标中定义的反应生物标志物将在这些模型中进一步验证。在具体目标3中，提出了两项基于患者的药物启动的临床试验：（i）厄洛替尼和达沙替尼在既往接受过治疗的NSCLC中的I期试验和（ii）达沙替尼在既往接受过治疗的NSCLC中的II期试验，沿着生物分子分析，基于我们在目标1&2中定义的初步数据和机制。

DESCRIPTION (provided by applicant): SRC proteins can link receptor tyrosine kinases to critical downstream oncogenic pathways such as PI3K/PTEN/Akt, STATs, and Ras/Raf/ERK. Regulation of these key pathways allows SRC to control cellular growth and proliferation, survival, invasion, and angiogenesis. Based on the importance of EGFR signaling in lung cancer and the known cooperation between EGFR and SRC proteins, we evaluated the effectiveness of novel SRC inhibitors in lung cancer cell lines with defined EGFR status. SRC inhibition reduces mutant EGFR lung cancer cell viability through the induction of apoptosis while having no significant apoptotic effect on cell lines with wildtype EGFR. The induction of apoptosis in EGFR mutant cell lines corresponds to downregulation of activated Akt and StatS survival proteins. In cell lines without EGFR mutation, SRC inhibition reduces cyclin D and increases p27 protein levels with a corresponding G1 cell cycle arrest. SRC inhibition also inhibits activated FAK and inhibits lung cancer cell invasion. These data demonstrate that novel SRC inhibitors could be effective therapy for patients with lung cancers, especially those driven by mutant EGFR proteins. The goal of this research proposal is to further characterize the effect of novel SRC kinase inhibitors in lung cancer cells. In specific aim 1, we will characterize the effect of SRC inhibitors on apoptosis and growth inhibition in lung cancer cells with defined EGFR status. We will evaluate the effects on key downstream pathways that control apoptosis and cell growth such as PI3K/PTEN/Akt and STATs. We will evaluate the effect of combined EGFR and SRC tyrosine kinase inhibitors on apoptosis and growth inhibition. In specific aim 2, we will evaluate the effect of SRC inhibition on tumor growth in vivo in lung cancer xenograft models with corresponding biomarker analysis. We plan to test the hypothesis that SRC inhibitor treatment of lung cancer xenografts with EGFR mutation will undergo tumor regression through enhanced apoptosis while treatment of xenografts with wildtype EGFR will result in growth inhibition. Biomarkers of response defined in the above aim will be further validated in these models. In specific aim 3, two investigator-initiated patient-based clinical trial trials are proposed: (i) a phase I trial of erlotinib and dasatinib in previously treated NSCLC and (ii) a phase II trial of dasatinib in previously treated NSCLC along with biomolecular analysis based on our preliminary data and mechanisms defined in Aims 1&2.