Antitumor Mechanisms of SRC Inhibitors in Lung Cancer

描述(申请人提供)：SRC蛋白可以将受体酪氨酸激酶连接到关键的下游致癌通路，如PI3K/PTEN/Akt、STATS和Ras/Raf/ERK。通过调控这些关键途径，SRC可以控制细胞的生长、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已知的EGFR和SRC蛋白之间的合作，我们评估了新型SRC抑制剂在具有明确EGFR状态的肺癌细胞系中的有效性。SRC抑制通过诱导凋亡降低突变的EGFR肺癌细胞的活力，而对野生型EGFR的细胞系没有明显的凋亡效应。诱导EGFR突变细胞系的凋亡与下调激活的Akt和STATS生存蛋白相对应。在没有EGFR突变的细胞系中，SRC抑制降低了细胞周期蛋白D，增加了p27蛋白水平，并相应地阻止了G1期细胞周期。SRC抑制也能抑制激活的FAK，抑制肺癌细胞的侵袭。这些数据表明，新的SRC抑制剂可以有效地治疗肺癌患者，特别是那些由突变的EGFR蛋白驱动的肺癌患者。这项研究计划的目标是进一步表征新型SRC激酶抑制剂在肺癌细胞中的作用。在特定的目标1中，我们将表征SRC抑制剂对具有明确EGFR状态的肺癌细胞的凋亡和生长抑制的影响。我们将评估PI3K/PTEN/Akt和STATS等控制细胞凋亡和生长的关键下游通路的作用。我们将评估联合使用EGFR和SRC酪氨酸激酶抑制剂对细胞凋亡和生长抑制的影响。在特定的目标2中，我们将通过相应的生物标志物分析来评估SRC抑制对肺癌移植瘤模型体内肿瘤生长的影响。我们计划验证这样的假设，即SRC抑制剂治疗带有EGFR突变的肺癌移植瘤将通过促进细胞凋亡而经历肿瘤消退，而治疗带有野生型EGFR的移植瘤将导致生长抑制。上述目标中定义的反应生物标记物将在这些模型中进一步得到验证。在具体目标3中，提出了两个由研究人员发起的以患者为基础的临床试验：(I)在先前治疗的非小细胞肺癌中使用erlotinib和dasatinib的I期试验，以及(Ii)先前治疗的NSCLC中使用达沙替尼的II期试验，以及基于我们的初步数据和AIMS 1和2中定义的机制的生物分子分析。

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.