J Cancer 2018; 9(24):4762-4773. doi:10.7150/jca.25138

Research Paper

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

Wenwen Chien1,2✉*, Makoto Sudo1*, Ling-Wen Ding1, Qiao-Yang Sun1, Peer Wuensche1, Kian Leong Lee1, Norimichi Hattori1, Manoj Garg1, Liang Xu1, Yun Zheng3, Sigal Gery2,4, Sarawut Wongphayak1, Henry Yang1, Erkan Baloglu5, Sharon Shacham5, Michael Kauffman5, Seiichi Mori1, H. Phillip Koeffler1,2,6

1. Cancer Science Institute of Singapore, National University of Singapore, Singapore
2. Department of Hematology-Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
3. State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
4. David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
5. Karyopharm Therapeutics, Boston, MA, USA
6. National University Cancer Institute, National University Hospital, Singapore
*These authors contributed equally to this work

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Citation:
Chien W, Sudo M, Ding LW, Sun QY, Wuensche P, Lee KL, Hattori N, Garg M, Xu L, Zheng Y, Gery S, Wongphayak S, Yang H, Baloglu E, Shacham S, Kauffman M, Mori S, Koeffler HP. Functional Genome-wide Screening Identifies Targets and Pathways Sensitizing Pancreatic Cancer Cells to Dasatinib. J Cancer 2018; 9(24):4762-4773. doi:10.7150/jca.25138. Available from http://www.jcancer.org/v09p4762.htm

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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.

Keywords: Pancreatic Cancer, Dasatinib, XPO