Therapeutic Mechanisms of Co-Targeting of EGFR and Src Family Kinases

头颈部鳞状细胞癌（SCCHN）生长失控的特征是获得了涉及表皮生长因子受体（EGFR）的自分泌调节途径。2006年，FDA批准EGFR单克隆抗体西妥昔单抗用于治疗SCCHN，使其成为45年来首个批准用于这种癌症的新药。然而，尽管EGFR在SCCHN肿瘤中普遍表达，但西妥昔单抗作为单药治疗的临床应答率有限。共同靶向EGFR阻断时激活的致癌通路与西妥昔单抗联合给药可增强治疗获益。 在上一个资助期，该项目专注于阐明SCCHN中G蛋白偶联受体（GPCR）和EGFR之间的相互作用，长期目标是设计一项结合EGFR和GPCR抑制剂用于头颈癌患者的临床试验。我们证明了Src家族激酶（SFK）在GPCR诱导的EGFR活化中的关键作用。在缺乏用于临床的泛GPCR抑制剂的情况下，我们选择在本次更新申请中将该项目重新聚焦于SFK和EGFR的共同靶向。新的初步数据还表明c-Met在EGFR耐药或阻断情况下活化。我们的工作假设是，在EGFR阻断的情况下，通过替代激酶的持续信号传导有助于SCCHN中EGFR靶向的有限临床应答。压倒一切的假设是，存在确定的替代途径，绕过癌细胞对EGFR信号传导的需要，并代表联合治疗的潜在靶点。我们已经确定的两个候选者是SFK和c-Met。这些研究的完成将阐明EGFR靶向策略的耐药机制，从而促进治疗方案的设计，以提高临床反应。我们将通过确定：1）EGFR抑制剂耐药SCCHN临床前模型中EGFR和Src家族激酶联合抑制的抗肿瘤机制; 2）HGF/c-Met信号传导在介导SCCHN对EGFR抑制的耐药性和/或作为SCCHN治疗的替代靶点中的作用; 3）西妥昔单抗联合达沙替尼在SCCHN患者中的治疗潜力。

The loss of growth control in squamous cell carcinoma of the head and neck (SCCHN) is characterized by acquisition of an autocrine regulatory pathway involving the epidermal growth factor receptor (EGFR). In 2006, the FDA approved the EGFR monoclonal antibody cetuximab for the treatment of SCCHN making it the first new drug approved for this cancer in 45 years. However, despite the ubiquitous expression of EGFR in SCCHN tumors, the clinical response rate to cetuximab as single agent therapy is limited. Co-targeting of oncogenic pathways that are activated in the setting of EGFR blockade in conjunction with cetuximab administration may enhance therapeutic benefits. In the previous funding period, this project focused on elucidating interactions between G-protein-coupled receptors (GPCR) and EGFR in SCCHN with the long-term goal of designing a clinical trial combining EGFR and GPCR inhibitors for head and neck cancer patients. We demonstrated the critical role of Src family kinases (SFK) in GPCR-induced EGFR activation. In the absence of a pan-GPCR inhibitor for clinical use, we have elected to refocus this project on co-targeting of SFK and EGFR in this renewal application. New preliminary data also implicates activation of c-Met in the setting of EGFR resistance or blockade. Our working hypothesis is that persistent signaling through alternate kinases in the setting of EGFR blockade contributes to the limited clinical responses to EGFR targeting in SCCHN. The over-riding hypothesis is that there are defined alternative pathways that bypass a cancer cell's need for EGFR signaling, and represent potential targets for combination therapy. The two candidates we have identified are SFK and c-Met. Completion of these studies will elucidate mechanisms of resistance to EGFR targeting strategies thus facilitating the design of therapeutic regimens to enhance clinical response. We will accomplish this goal by determining: 1) the anti-tumor mechanisms of combined inhibition of EGFR and Src family kinases in SCCHN preclinical models of EGFR inhibitor resistance; 2) the role of HGF/c-Met signaling in mediating resistance of SCCHN to EGFR inhibition and/or as an alternative target for SCCHN therapy; and 3) the therapeutic potential of cetuximab plus dasatinib in SCCHN patients.