Illuminating biological pathways for drug targeting in head and neck squamous cell carcinoma

Head and neck squamous cell carcinoma (HNSCC) remains a morbid disease with poor prognosis and treatment that typically leaves patients with permanent damage to critical functions such as eating and talking. Currently only three targeted therapies are FDA approved for use in HNSCC, two of which are recently approved immunotherapies. In this work, we identify biological pathways involved with this disease that could potentially be targeted by current FDA approved cancer drugs and thereby expand the pool of potential therapies for use in HNSCC treatment. We analyzed 508 HNSCC patients with sequencing information from the Genomic Data Commons (GDC) database and assessed which biological pathways were significantly enriched for somatic mutations or copy number alterations. We then further classified pathways as either “light” or “dark” to the current reach of FDA-approved cancer drugs using the Cancer Targetome, a compendium of drug-target information. Light pathways are statistically enriched with somatic mutations (or copy number alterations) and contain one or more targets of current FDA-approved cancer drugs, while dark pathways are enriched with somatic mutations (or copy number alterations) but not currently targeted by FDA-approved cancer drugs. Our analyses indicated that approximately 35–38% of disease-specific pathways are in scope for repurposing of current cancer drugs. We further assess light and dark pathways for subgroups of patient tumor samples according to HPV status. The framework of light and dark pathways for HNSCC-enriched biological pathways allows us to better prioritize targeted therapies for further research in HNSCC based on the HNSCC genetic landscape and FDA-approved cancer drug information. We also highlight the importance in the identification of sub-pathways where targeting and cross targeting of other pathways may be most beneficial to predict positive or negative synergy with potential clinical significance. This framework is ideal for precision drug panel development, as well as identification of highly aberrant, untargeted candidates for future drug development.头颈部鳞状细胞癌（Head and neck squamous cell carcinoma, HNSCC）仍是一种预后不佳、治疗手段有限的致死性疾病，通常会造成患者进食、言语等关键生理功能的永久性损伤。目前仅三款靶向疗法获美国食品药品监督管理局（Food and Drug Administration, FDA）批准用于HNSCC治疗，其中两款为近年获批的免疫疗法。本研究旨在识别与该疾病相关的生物学通路，这些通路可被当前已获FDA批准的抗癌药物靶向，从而扩充可用于HNSCC治疗的潜在疗法库。我们分析了来自基因组数据共享库（Genomic Data Commons, GDC）的508例HNSCC患者的测序数据，评估了哪些生物学通路存在显著的体细胞突变或拷贝数变异富集。随后我们借助癌症靶标组（Cancer Targetome）——一款收录药物-靶点信息的综合汇编——将通路依据当前FDA批准的抗癌药物覆盖范围划分为“亮通路”与“暗通路”：亮通路指存在体细胞突变（或拷贝数变异）富集，且包含一个或多个当前FDA批准抗癌药物靶点的通路；暗通路则指存在体细胞突变（或拷贝数变异）富集，但未被当前FDA批准的抗癌药物靶向的通路。分析结果显示，约35%~38%的疾病特异性通路可通过现有抗癌药物的重定位开发新疗法。我们还根据患者肿瘤样本的人乳头瘤病毒（Human Papillomavirus, HPV）感染状态，对亮、暗通路进行了亚组分析。本研究提出的HNSCC富集生物学通路的亮/暗通路分类框架，可基于HNSCC的遗传特征与FDA批准抗癌药物信息，更好地为HNSCC靶向疗法的后续研究确定优先级。此外我们还强调了识别亚通路的重要性：在这些亚通路中，对其他通路的靶向或交叉靶向或可最有效地预测具有临床意义的正向与负向协同效应。该框架非常适用于精准药物研发组合的开发，同时也可用于识别高度异常且尚未被靶向的候选靶点，用于未来的药物研发。