An FGFR1 oncogene driver pathway in head and neck cancer

描述（由申请人提供）： 头颈部鳞状细胞癌（HNSCC）是全球第六大最常见的癌症，尽管优化了细胞毒性治疗，但转移性疾病的5年生存率仍然很低。对于播散性疾病，显然需要新的靶点和疗法。受体酪氨酸激酶（RTK）是有吸引力的癌症靶标，这是由于：1）通过突变、扩增和/或自分泌/旁分泌激活的频繁失调，2）在致癌信号通路中的近端定位和3）小分子酪氨酸激酶抑制剂（TKI）和抑制性抗体的特异性靶向。迄今为止，靶向治疗尚未有效地应用于HNSCC，部分原因是缺乏关于显性致癌基因驱动因子的信息。虽然抑制性EGFR抗体西妥昔单抗被批准用于HNSCC，但总体效果是适度的，可能是由于未能选择EGFR成瘾的HNSCC和/或快速获得耐药性。虽然基因组学方法提供了关于HNSCC相关肿瘤抑制因子的新信息，但通常未鉴定出频繁突变的癌基因驱动因子。这一观察结果提出了一个问题，即靶向治疗是否可以成功地应用于这种癌症。我们发表的研究结果确定了一个对FGFR抑制剂高度敏感的HNSCC细胞系亚群以及一个对EGFR特异性TKI敏感的亚群。此外，我们发表的和初步的研究结果揭示了FGFR在EGFR特异性抑制剂获得性耐药中的假定作用。总之，这些结果支持FGFR自分泌途径是HNSCC亚组中的显性致癌基因驱动的假设。此外，特异性FGFR是HNSCC中EGFR抑制剂的获得性或内在耐药机制的候选者。为了验证这些假设，我们将完成这些目标：目标1。定义在HNSCC细胞系和在裸鼠中直接繁殖的原发性HNSCC肿瘤中作为驱动因子发挥作用的活性FGFR和FGF。此外，将定义存档的HNSCC肿瘤中FGFR通路表达的流行率。我们将测试的假设，FGFR 1和特定的FGF和蛋白聚糖共受体的致癌基因驱动途径的功能，在临床相关的部分头颈部肿瘤的组成部分。目标2.定义HNSCC中EGFR抑制剂耐药的FGFR依赖性和新机制。我们的研究显示在用EGFR特异性抑制剂处理后EGFR依赖性HNSCC细胞中FGFR 2和FGFR 3的快速诱导以及在EGFR依赖性HNSCC细胞系对吉非替尼的获得性抗性期间FGFR 1和FGF 2的较慢适应性诱导。我们假设EGFR靶向治疗未能提供HNSCC的长期控制是由于多种辅助生长途径降低了EGFR单独抑制的疗效。这些特定目标的完成预计将揭示FGFR途径作为HNSCC的新治疗靶点。正在进行的多种FGFR抑制剂的早期临床开发可以为其快速应用于这种与退伍军人群体高度相关的癌症奠定基础。

DESCRIPTION (provided by applicant): Head and neck squamous cell carcinoma (HNSCC) is the sixth most frequent cancer worldwide and despite optimized cytotoxic therapies, the 5-year survival rate of metastatic disease remains poor. Novel targets and therapies are clearly needed for disseminated disease. Receptor tyrosine kinases (RTKs) are attractive cancer targets due to: 1) frequent deregulation via mutation, amplification and/or autocrine/paracrine activation, 2) proximal positioning in oncogenic signal pathways and 3) specific targeting by small molecule tyrosine kinase inhibitors (TKIs) and inhibitory antibodies. To date, targeted therapies have not been effectively applied to HNSCC due, in part, to paucity of information on the dominant oncogene drivers. While the inhibitory EGFR antibody, cetuximab, is approved for use in HNSCC, overall effects are modest, likely due to failure to select for EGFR-addicted HNSCCs and/or rapid acquisition of resistance. While genomic approaches provide new information regarding tumor suppressors relevant to HNSCC, frequently mutated oncogene drivers were not generally identified. This observation raises the question of whether targeted therapeutics can, in fact, be successfully applied to this cancer. Our published findings identify a subset of HNSCC cell lines that is highly sensitive to FGFR inhibitors as well as a subset that is sensitive to EGFR-specific TKIs. In addition, our published and preliminary findings reveal putative roles for FGFRs in acquired resistance to EGFR-specific inhibitors. Together, these results support a hypothesis that an FGFR autocrine pathway is a dominant oncogene driver in a subset of HNSCCs. Moreover, specific FGFRs are candidates for acquired or intrinsic resistance mechanisms to EGFR inhibitors in HNSCC. To test these hypotheses, we will complete these Aims: Aim 1. Define the active FGFRs and FGFs that function as drivers in HNSCC cell lines and in primary HNSCC tumors directly propagated in nude mice. Also, the prevalence of FGFR pathway expression in archived HNSCC tumors will be defined. We will test the hypothesis that FGFR1 and specific FGFs and proteoglycan co-receptors are components of an oncogene driver pathway that functions in a clinically relevant fraction of head and neck tumors. Aim 2. Define FGFR-dependent and novel mechanisms of resistance to EGFR inhibitors in HNSCC. Our studies show rapid induction of FGFR2 and FGFR3 in EGFR- dependent HNSCC cells following treatment with EGFR-specific inhibitors as well as slower adaptive induction of FGFR1 and FGF2 during acquired resistance of EGFR-dependent HNSCC cell lines to gefitinib. We hypothesize that the failure of EGFR-targeted therapies to provide long-term control of HNSCC is due to multiple auxiliary growth pathways that reduce efficacy of EGFR inhibition alone. Completion of these specific aims is anticipated to unveil FGFR pathways as novel therapeutic targets in HNSCC. The ongoing early clinical development of multiple FGFR inhibitors could set the stage for their rapid application to this cancer that is highly relevant to the veteran population.