P3 - Antitumor Mechanisms of SRC Inhibitors in Lung Cancer

SRC蛋白可以将受体酪氨酸激酶与关键的下游致癌途径，如 PI3K/PTEN/Akt、STAT和Ras/Raf/ERK。这些关键通路的调节使SRC能够控制细胞 生长和增殖、存活、侵袭和血管生成。基于EGFR信号传导的重要性 在肺癌和EGFR和SRC蛋白之间已知的合作，我们评估了有效性 新型SRC抑制剂在具有确定EGFR状态的肺癌细胞系中的应用。SRC抑制减少突变 EGFR通过诱导肺癌细胞凋亡而对细胞生存力无明显的凋亡作用 在具有野生型EGFR的细胞系上。EGFR突变细胞系中的细胞凋亡诱导对应于 下调激活的Akt和Stat 3存活蛋白。在无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，同时相应的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。这些数据证明 新的SRC抑制剂可能是肺癌患者的有效治疗方法，特别是那些由 突变EGFR蛋白。本研究的目的是进一步描述新型SRC的作用 肺癌细胞中的激酶抑制剂。在具体目标1中，我们将表征SRC抑制剂对以下的影响： 在具有确定的EGFR状态的肺癌细胞中的细胞凋亡和生长抑制。我们将评估 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。 我们将评估EGFR和SRC酪氨酸激酶抑制剂联合应用对细胞凋亡和生长的影响。 抑制作用新的生物标志物将通过磷酸化蛋白质组学鉴定。具体目标2： 评价SRC抑制对肺癌异种移植模型中体内肿瘤生长的影响， 相应的生物标志物分析。我们计划验证SRC抑制剂治疗肺 具有EGFR突变的癌症异种移植物将通过增强的细胞凋亡而经历肿瘤消退， 用野生型EGFR处理异种移植物将导致生长抑制。定义的缓解生物标志物 在上述目标将进一步验证在这些模型。在具体目标3中，我们将开展一项由 厄洛替尼和达沙替尼在既往接受过治疗的NSCLC患者中的II期临床试验，沿着 基于目标1&2中定义的机制的生物分子分析。

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 Stat3 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. Novel biomarkers will be identified through phospho-proteomics. 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, we will conduct an investigatorinitiated patient-based phase II trial of erlotinib &dasatinib in previously treated NSCLC along with biomolecular analysis based on mechanisms defined in Aims 1&2.