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
✉ Corresponding author
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. https://www.jcancer.org/v09p4762.htm
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
Citation styles
APA
Chien, W., Sudo, M., Ding, L.W., Sun, Q.Y., Wuensche, P., Lee, K.L., Hattori, N., Garg, M., Xu, L., Zheng, Y., Gery, S., Wongphayak, S., Yang, H., Baloglu, E., Shacham, S., Kauffman, M., Mori, S., Koeffler, H.P. (2018). Functional Genome-wide Screening Identifies Targets and Pathways Sensitizing Pancreatic Cancer Cells to Dasatinib. Journal of Cancer, 9(24), 4762-4773. https://doi.org/10.7150/jca.25138.
ACS
Chien, W.; Sudo, M.; Ding, L.W.; Sun, Q.Y.; Wuensche, P.; Lee, K.L.; Hattori, N.; Garg, M.; Xu, L.; Zheng, Y.; Gery, S.; Wongphayak, S.; Yang, H.; Baloglu, E.; Shacham, S.; Kauffman, M.; Mori, S.; Koeffler, H.P. 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.
NLM
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. https://www.jcancer.org/v09p4762.htm
CSE
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. 2018. Functional Genome-wide Screening Identifies Targets and Pathways Sensitizing Pancreatic Cancer Cells to Dasatinib. J Cancer. 9(24):4762-4773.
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