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)是全球第六大常见癌症，尽管优化了细胞毒治疗，但转移性疾病的5年存活率仍然很低。显然，传播疾病需要新的靶点和治疗方法。受体酪氨酸激酶(RTK)是一种很有吸引力的肿瘤靶点，因为：1)突变、扩增和/或自分泌/旁分泌激活导致的频繁去调节；2)肿瘤信号通路的近端定位；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。到目前为止，靶向治疗还没有有效地应用于HNSCC，部分原因是缺乏关于主要癌基因驱动因素的信息。虽然抑制性EGFR抗体西妥昔单抗被批准用于HNSCC，但总体影响不大，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与HNSCC相关的肿瘤抑制基因的新信息，但通常没有发现频繁突变的癌基因驱动因素。这一观察结果提出了一个问题，即靶向治疗实际上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对FGFR抑制剂高度敏感的HNSCC细胞系的子集，以及对EGFR特异性TKI敏感的子集。此外，我们已发表的和初步的发现揭示了FGFRs在对EGFR特异性抑制剂的获得性耐药性中的假定作用。综上所述，这些结果支持一种假设，即FGFR自分泌途径是HNSCs的一个子集中的显性癌基因驱动因素。此外，在HNSCC中，特定的FGFR是对EGFR抑制剂的获得性或内在耐药机制的候选者。为了验证这些假说，我们将完成这些目标：目的1.确定在HNSCC细胞系和直接在裸鼠体内传播的原发HNSCC肿瘤中起驱动作用的活性FGFRs和FGFs。此外，还将确定FGFR途径在存档的HNSCC肿瘤中的表达情况。我们将检验这一假设，即FGFR1和特定的FGFs和蛋白多糖共受体是癌基因驱动途径的组成部分，该途径在头颈部肿瘤的临床相关部分发挥作用。目的2.明确HNSCC中FGFR依赖和对EGFR抑制剂耐药的新机制。我们的研究表明，在EGFR依赖的HNSCC细胞中，经EGFR特异性抑制剂处理后，FGFR2和FGFR3迅速诱导，而在EGFR依赖的HNSCC细胞株对吉非替尼的获得性耐药期间，FGFR1和FGF2的适应性诱导较慢。我们假设，EGFR靶向治疗未能提供对HNSCC的长期控制是由于多种辅助生长途径降低了单独抑制EGFR的疗效。这些特定目标的完成有望揭开FGFR通路作为HNSCC治疗新靶点的面纱。正在进行的多种FGFR抑制剂的早期临床开发可能为它们快速应用于这种与退伍军人人群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.