EGFRvIII expression, signaling and treatment in SCC of the head and neck

描述(申请人提供)：口腔头颈部鳞状细胞癌(OSCC)是美国第六大最常见的癌症。需要开发更有针对性的治疗方法来降低这种癌症的高死亡率。表皮生长因子受体(EGFR)已成为口腔鳞癌可能的治疗靶点。这种酪氨酸激酶受体的过度表达已经在口腔鳞癌中表现出来，并被发现存在于高达90%的肿瘤中，其中表达水平与患者生存期的下降有关。2006年，西妥昔单抗(Erbitux；Imclone Systems)(一种EGFR特异性单抗)成为45年来FDA批准的第一种治疗SCCHN的新疗法。尽管口腔鳞癌中普遍存在EGFR的表达，但西妥昔单抗作为单一药物的临床反应有限(~10%)。抵抗野生型EGFR阻断的一个潜在机制是表达具有结构性活性的EGF受体变异体3(EGFRvIII)。Sok等人。(2006)报道了大约40%的SCCHN中存在EGFRvIII，并在体外和体内证明了表达EGFRvIII的细胞对西妥昔单抗的耐药性。在胶质瘤中，STAT3和Src家族激酶(SFKs)已被阐明为EGFRvIII致癌表型中的关键调控蛋白。EGFRvIII蛋白在口腔鳞癌中的表达机制尚不清楚。此外，在SCCHN中，通过EGFRvIII介导的差异信号通路仍然相对未知。我推测，导致口腔鳞癌中EGFRvIII表达的机制是外显子2-7的mRNA剪接位点的改变，导致EGFR转录本的交替剪接。此外，我假设EGFRvIII通过STAT3和SFK特异的信号转导有助于EGFRvIII的致癌表型，并且阻断这些调控元件将导致对EGFR靶向药物的增强反应。 公共卫生相关性：口腔鳞状细胞癌是一种高死亡率和高发病率的破坏性疾病。目前口腔鳞癌的治疗方法仍然有限，许多患者表现出对治疗的抵抗力。本文提出的工作将阐明对治疗耐药途径的更透彻的理解，并有助于设计更有效的治疗方案。

DESCRIPTION (provided by applicant): Oral squamous cell carcinoma of the head and neck (OSCC) is the sixth most common cancer in the United States. Development of more targeted therapies is needed to reduce the high mortality rate seen with this cancer. Epidermal Growth Factor Receptor (EGFR) has emerged as a plausible therapeutic target for OSCC. Overexpression of this tyrosine kinase receptor has been characterized in OSCC and found to be present in up to ~90% of tumors where expression levels correlate with decreased patient survival. In 2006 cetuximab (Erbitux; Imclone Systems) (an EGFR specific monoclonal antibody) became the first new FDA-approved treatment for SCCHN in 45 years. Despite ubiquitous EGFR expression in OSCC, cetuximab has demonstrated limited clinical responses as a single agent (~10%). One potential mechanism of resistance to the wild type EGFR blockade is the expression of the constitutively active EGF receptor variant 3 (EGFRvIII). Sok et al. (2006) reported the presence of EGFRvIII in approximately 40% of SCCHN, and demonstrated in vitro and in vivo resistance of EGFRvIII expressing cells to cetuximab. In glioma (where EGFRvIII has been best characterized) STAT3 and Src family kinases (SFKs) have been elucidated as key regulatory proteins in the oncogenic phenotype of EGFRvIII. The mechanism of EGFRvIII protein expression is still unexplored in OSCC. Additionally, differential signaling pathways mediated through EGFRvIII remain relatively uncharacterized in SCCHN. I hypothesize that the mechanism contributing to EGFRvIII expression in OSCC is alteration of the mRNA splice sites for exons 2-7 causing alternate splicing of the EGFR transcript. Further, I hypothesize that EGFRvIII specific signaling through STAT3 and SFKs contributes to the oncogenic phenotype of EGFRvIII and that blocking these regulatory elements will lead to enhanced response to EGFR targeting agents. PUBLIC HEALTH RELEVANCE: OSCC is a devastating disease with high mortality and morbidity. Current treatments for OSCC are still limited with many patients demonstrating resistance to treatment. The work proposed here will elucidate a more thorough understanding of the pathways of therapeutic resistance and facilitate the design of more effective treatment regimens.