Deneka Alexander Y, Einarson Margret B, Bennett John, Nikonova Anna S, Elmekawy Mohamed, Zhou Yan, Lee Jong Woo, Burtness Barbara A, Golemis Erica A
Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Department of Biochemistry and Biotechnology, Kazan Federal University, 420000 Kazan, Russia.
Cancers (Basel). 2020 Jan 28;12(2):306. doi: 10.3390/cancers12020306.
Head and neck squamous cell carcinomas (HNSCC) affect more than 800,000 people annually worldwide, causing over 15,000 deaths in the US. Among HNSCC cancers, human papillomavirus (HPV)-negative HNSCC has the worst outcome, motivating efforts to improve therapy for this disease. The most common mutational events in HPV-negative HNSCC are inactivation of the tumor suppressors (>85%) and (>57%), which significantly impairs G1/S checkpoints, causing reliance on other cell cycle checkpoints to repair ongoing replication damage. We evaluated a panel of cell cycle-targeting clinical agents in a group of HNSCC cell lines to identify a subset of drugs with single-agent activity in reducing cell viability. Subsequent analyses demonstrated potent combination activity between the CHK1/2 inhibitor LY2606268 (prexasertib), which eliminates a G2 checkpoint, and the WEE1 inhibitor AZD1775 (adavosertib), which promotes M-phase entry, in induction of DNA damage, mitotic catastrophe, and apoptosis, and reduction of anchorage independent growth and clonogenic capacity. These phenotypes were accompanied by more significantly reduced activation of CHK1 and its paralog CHK2, and enhanced CDK1 activation, eliminating breaks on the mitotic entry of cells with DNA damage. These data suggest the potential value of dual inhibition of CHK1 and WEE1 in tumors with compromised G1/S checkpoints.
头颈部鳞状细胞癌（HNSCC）每年在全球影响超过80万人，在美国导致超过15000人死亡。在HNSCC癌症中，人乳头瘤病毒（HPV）阴性的HNSCC预后最差，这促使人们努力改善该疾病的治疗方法。HPV阴性HNSCC中最常见的突变事件是肿瘤抑制因子（>85%）和（>57%）失活，这会显著损害G1/S检查点，导致依赖其他细胞周期检查点来修复正在进行的复制损伤。我们在一组HNSCC细胞系中评估了一组靶向细胞周期的临床药物，以确定具有单药活性降低细胞活力的药物子集。随后的分析表明，消除G2检查点的CHK1/2抑制剂LY2606268（普瑞赛替尼）和促进M期进入的WEE1抑制剂AZD1775（阿伐司他）在诱导DNA损伤、有丝分裂灾难和细胞凋亡以及降低锚定非依赖性生长和克隆形成能力方面具有强大的联合活性。这些表型伴随着CHK1及其旁系同源物CHK2的激活更显著降低，以及CDK1激活增强，消除了DNA损伤细胞进入有丝分裂时的断裂。这些数据表明，在G1/S检查点受损的肿瘤中，双重抑制CHK1和WEE1具有潜在价值。
