Yau Edwin H, Kummetha Indrasena Reddy, Lichinchi Gianluigi, Tang Rachel, Zhang Yunlin, Rana Tariq M
Department of Pediatrics and Institute for Genomic Medicine, University of California San Diego School of Medicine, La Jolla, California.
Division of Hematology-Oncology, Department of Internal Medicine, University of California San Diego School of Medicine, La Jolla, California.
Cancer Res. 2017 Nov 15;77(22):6330-6339. doi: 10.1158/0008-5472.CAN-17-2043. Epub 2017 Sep 27.
Targeting mutant KRAS signaling pathways continues to attract attention as a therapeutic strategy for KRAS-driven tumors. In this study, we exploited the power of the CRISPR-Cas9 system to identify genes affecting the tumor xenograft growth of human mutant KRAS (KRAS) colorectal cancers. Using pooled lentiviral single-guide RNA libraries, we conducted a genome-wide loss-of-function genetic screen in an isogenic pair of human colorectal cancer cell lines harboring mutant or wild-type KRAS. The screen identified novel and established synthetic enhancers or synthetic lethals for KRAS colorectal cancer, including targetable metabolic genes. Notably, genetic disruption or pharmacologic inhibition of the metabolic enzymes NAD kinase or ketohexokinase was growth inhibitory In addition, the chromatin remodeling protein INO80C was identified as a novel tumor suppressor in KRAS colorectal and pancreatic tumor xenografts. Our findings define a novel targetable set of therapeutic targets for KRAS tumors. .
作为KRAS驱动肿瘤的治疗策略，靶向突变型KRAS信号通路一直备受关注。在本研究中，我们利用CRISPR-Cas9系统的强大功能来鉴定影响人突变型KRAS（KRAS）结直肠癌肿瘤异种移植生长的基因。我们使用慢病毒单导向RNA文库，在一对携带突变型或野生型KRAS的同基因人结肠癌细胞系中进行了全基因组功能丧失遗传筛选。该筛选鉴定出了KRAS结直肠癌的新的和已确定的合成增强子或合成致死基因，包括可靶向的代谢基因。值得注意的是，代谢酶NAD激酶或己酮糖激酶的基因破坏或药理抑制具有生长抑制作用。此外，染色质重塑蛋白INO80C被鉴定为KRAS结直肠癌和胰腺肿瘤异种移植中的一种新型肿瘤抑制因子。我们的研究结果定义了一组针对KRAS肿瘤的新的可靶向治疗靶点。
