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  • Functional Genome-wide Screening Identifies Targets and Pathways Sensitizing Pancreatic Cancer Cells to Dasatinib.

Functional Genome-wide Screening Identifies Targets and Pathways Sensitizing Pancreatic Cancer Cells to Dasatinib.

Journal of Cancer (2018-12-28)
Wenwen Chien, Makoto Sudo, Ling-Wen Ding, Qiao-Yang Sun, Peer Wuensche, Kian Leong Lee, Norimichi Hattori, Manoj Garg, Liang Xu, Yun Zheng, Sigal Gery, Sarawut Wongphayak, Henry Yang, Erkan Baloglu, Sharon Shacham, Michael Kauffman, Seiichi Mori, H Phillip Koeffler
PMID30588262
ABSTRACT

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.