Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
UPMC Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
Clin Cancer Res. 2021 Nov 15;27(22):6250-6264. doi: 10.1158/1078-0432.CCR-20-4789. Epub 2021 Aug 18.
Human papillomavirus (HPV) infection drives the development of some head and neck squamous cell carcinomas (HNSCC). This disease is rapidly increasing in incidence worldwide. Although these tumors are sensitive to treatment, approximately 10% of patients fail therapy. However, the mechanisms that underlie treatment failure remain unclear.
We performed RNA sequencing (RNA-seq) on tissues from matched primary- (pHNSCC) and metachronous-recurrent cancers (rHNSCC) to identify transcriptional differences to gain mechanistic insight into the evolutionary adaptations of metachronous-recurrent tumors. We used HPV-related HNSCC cells lines to investigate the effect of (i) NRF2 overexpression on growth and , (ii) oxidative phosphorylation (OXPHOS) inhibition using IACS-010759 on NRF2-dependent cells, and (iii) combination of cisplatin and OXPHOS inhibition.
The OXPHOS pathway is enriched in recurrent HPV-associated HNSCC and may contribute to treatment failure. NRF2-enriched HNSCC samples from The Cancer Genome Atlas (TCGA) with enrichment in OXPHOS, fatty-acid metabolism, Myc, Mtor, reactive oxygen species (ROS), and glycolytic signaling networks exhibited worse survival. HPV-positive HNSCC cells demonstrated sensitivity to the OXPHOS inhibitor, in a NRF2-dependent manner. Further, using murine xenograft models, we identified NRF2 as a driver of tumor growth. Mechanistically, NRF2 drives ROS and mitochondrial respiration, and NRF2 is a critical regulator of redox homeostasis that can be crippled by disruption of OXPHOS. NRF2 also mediated cisplatin sensitivity in endogenously overexpressing primary HPV-related HNSCC cells.
These results unveil a paradigm-shifting translational target harnessing NRF2-mediated metabolic reprogramming in HPV-related HNSCC.
人乳头瘤病毒（HPV）感染可导致部分头颈部鳞状细胞癌（HNSCC）的发生。这种疾病在全球的发病率正在迅速上升。尽管这些肿瘤对治疗敏感，但约有 10%的患者治疗失败。然而，导致治疗失败的机制仍不清楚。
我们对配对的原发（pHNSCC）和继发复发性肿瘤（rHNSCC）组织进行了 RNA 测序（RNA-seq），以确定转录差异，从而深入了解继发复发性肿瘤的进化适应机制。我们使用 HPV 相关的 HNSCC 细胞系来研究（i）NRF2 过表达对细胞生长的影响，（ii）使用 IACS-010759 抑制氧化磷酸化（OXPHOS）对 NRF2 依赖性细胞的影响，以及（iii）顺铂与 OXPHOS 抑制联合应用的影响。
OXPHOS 通路在复发性 HPV 相关 HNSCC 中富集，可能导致治疗失败。TCGA 中 NRF2 富集、OXPHOS、脂肪酸代谢、Myc、Mtor、活性氧（ROS）和糖酵解信号网络富集的 HNSCC 样本的生存情况较差。HPV 阳性 HNSCC 细胞对 OXPHOS 抑制剂敏感，且这种敏感性依赖于 NRF2。此外，我们在小鼠异种移植模型中发现 NRF2 是肿瘤生长的驱动因素。从机制上讲，NRF2 驱动 ROS 和线粒体呼吸，是氧化还原平衡的关键调节因子，其可被 OXPHOS 破坏所削弱。NRF2 还介导了内源性过表达原发性 HPV 相关 HNSCC 细胞对顺铂的敏感性。
这些结果揭示了一种具有变革性的转化靶点，可利用 HPV 相关 HNSCC 中的 NRF2 介导的代谢重编程。
