de Jong Mathilde Rikje Willemijn, Langendonk Myra, Reitsma Bart, Herbers Pien, Nijland Marcel, Huls Gerwin, van den Berg Anke, Ammatuna Emanuele, Visser Lydia, van Meerten Tom
Department of Hematology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, the Netherlands.
Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, the Netherlands.
Cancers (Basel). 2019 Nov 7;11(11):1743. doi: 10.3390/cancers11111743.
Genomically unstable cancers are dependent on specific cell cycle checkpoints to maintain viability and prevent apoptosis. The cell cycle checkpoint protein WEE1 is highly expressed in genomically unstable cancers, including diffuse large B-cell lymphoma (DLBCL). Although WEE1 inhibition effectively induces apoptosis in cancer cells, the effect of WEE1 inhibition on anti-apoptotic dependency is not well understood. We show that inhibition of WEE1 by AZD1775 induces DNA damage and pre-mitotic entry in DLBCL, thereby enhancing dependency on BCL-2 and/or MCL-1. Combining AZD1775 with anti-apoptotic inhibitors such as venetoclax (BCL-2i) or S63845 (MCL-1i) enhanced sensitivity in a cell-specific manner. In addition, we demonstrate that both G2/M cell cycle arrest and DNA damage induction put a similar stress on DLBCL cells, thereby enhancing anti-apoptotic dependency. Therefore, genotoxic or cell cycle disrupting agents combined with specific anti-apoptotic inhibitors may be very effective in genomic unstable cancers such as DLBCL and therefore warrants further clinical evaluation.
基因组不稳定的癌症依赖于特定的细胞周期检查点来维持生存能力并防止细胞凋亡。细胞周期检查点蛋白WEE1在基因组不稳定的癌症中高度表达，包括弥漫性大B细胞淋巴瘤（DLBCL）。尽管抑制WEE1能有效诱导癌细胞凋亡，但WEE1抑制对抗凋亡依赖性的影响尚不清楚。我们发现，AZD1775抑制WEE1会在DLBCL中诱导DNA损伤和有丝分裂前期进入，从而增强对BCL-2和/或MCL-1的依赖性。将AZD1775与抗凋亡抑制剂如维奈克拉（BCL-2i）或S63845（MCL-1i）联合使用，以细胞特异性方式增强了敏感性。此外，我们证明G2/M期细胞周期阻滞和DNA损伤诱导对DLBCL细胞施加了类似的压力，从而增强了抗凋亡依赖性。因此，基因毒性或细胞周期破坏剂与特定的抗凋亡抑制剂联合使用，可能对DLBCL等基因组不稳定的癌症非常有效，因此值得进一步的临床评估。
