Chien Wenwen, Sudo Makoto, Ding Ling-Wen, Sun Qiao-Yang, Wuensche Peer, Lee Kian Leong, Hattori Norimichi, Garg Manoj, Xu Liang, Zheng Yun, Gery Sigal, Wongphayak Sarawut, Yang Henry, Baloglu Erkan, Shacham Sharon, Kauffman Michael, Mori Seiichi, Koeffler H Phillip
Cancer Science Institute of Singapore, National University of Singapore, Singapore.
Department of Hematology-Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
J Cancer. 2018 Dec 10;9(24):4762-4773. doi: 10.7150/jca.25138. eCollection 2018.
This study is an unbiased genomic screen to obtain functional targets for increased effectiveness of dasatinib in pancreatic cancer. Dasatinib, a multi-targeted tyrosine kinase inhibitor, is used in clinical trials for treatment of pancreatic cancer; however, intrinsic and acquired resistance often occurs. We used a dasatinib-resistant pancreatic cancer cell line SU8686 to screen for synthetic lethality that synergizes with dasatinib using a pooled human shRNA library followed by next generation sequencing. Novel genes were identified which when silenced produced a prominent inhibitory effect with dasatinib against the pancreatic cancer cells. Several of these genes are involved in the regulation of epigenetics, as well as signaling pathways of the FOXO and hedgehog families. Small molecule inhibitors of either histone deacetylases or nuclear exporter had marked inhibitory effect with dasatinib in pancreatic cancers, suggesting their potential therapeutic effectiveness in this deadly cancer.
本研究是一项无偏倚的基因组筛选，旨在获得能提高达沙替尼治疗胰腺癌有效性的功能靶点。达沙替尼是一种多靶点酪氨酸激酶抑制剂，正在用于胰腺癌治疗的临床试验；然而，内在性和获得性耐药经常出现。我们使用一株对达沙替尼耐药的胰腺癌细胞系SU8686，通过汇集的人源shRNA文库及二代测序来筛选与达沙替尼协同作用的合成致死性。鉴定出了一些新基因，这些基因沉默时会与达沙替尼对胰腺癌细胞产生显著的抑制作用。其中一些基因参与表观遗传学调控以及FOXO和刺猬蛋白家族的信号通路。组蛋白去乙酰化酶或核输出蛋白的小分子抑制剂与达沙替尼联合对胰腺癌有显著抑制作用，提示它们在这种致命癌症中具有潜在的治疗效果。
