沈仲燮教授

[Exploiting synthetic lethality for cancer precision medicine]

Synthetic lethality is a genetic interaction where a single gene deficiency is tolerable for cell viability while the combination of deficiencies in two genes leads to cell death. The concept of the synthetic lethality has been widely exploited in cancer research field because a large portion of cancer has loss-of-function mutations in tumor suppressor genes. Synthetic lethality utilizes the mutations in tumor suppressor genes as a mark for selectivity of anticancer drugs. Pharmacological or genetic perturbation of a synthetic lethality partner of a tumor suppressor will cause selective lethality of the cancer cells that carry the tumor suppressor mutation. As it provides a strong cancer cell selectivity, synthetic lethality is one of core approaches for cancer precision medicine.

My lab is studying major tumor suppressor genes, including p53, PTEN, RB1, BRCA1, ARID1A, and SMAD4, and is expanding to newly identified tumor suppressors. We have established isogenic cell pairs for the tumor suppressor genes and actively working on identifying synthetic lethality partners using chemical and genetic screenings.

1. Shi, C., Yang, E. J., Liu, Y., Mou, P. K, Ren, G., Shim, J. S. (2020) Bromodomain and Extra-Terminal Motif (BET) Inhibition is Synthetic Lethal with Loss of SMAD4 in Colorectal Cancer Cells via Restoring the Loss of MYC Repression. Oncogene (Accepted)
2. Hwang, H. Y., Shim, J. S., Kim, D., and Kwon, H. J. (2020) Antidepressant Drug Sertraline Modulates AMPK-MTOR Signaling-Mediated Autophagy via Targeting Mitochondrial VDAC1 Protein. Autophagy
3. Lyu, J. F., Yang, E. J., Zhang, B. Y., Wu, C. J., Pardeshi, L., Shi, C. X., Mou, P. K., Liu, Y. F., Tan, K. L., and Shim, J. S. (2020) Synthetic Lethality of RB1 and Aurora A is Driven by Stathmin-Mediated Disruption of Microtubule Dynamics. Nat Commun 11 (1), 5105
4. Zhang, B. Y., Lyu, J. F., Yang, E. J., Liu, Y. F., Wu, C. J., Pardeshi, L., Tan, K. L., Chen, Q., Xu, X. L., Deng, C. X., and Shim, J. S. (2020) Class I Histone Deacetylase Inhibition Is Synthetic Lethal with BRCA1 Deficiency in Breast Cancer Cells. Acta Pharm Sin B 10, 615-627
5. Liu, Y. F., Yang, E. J., Shi, C. X., Mou, P. K., Zhang, B. Y., Wu, C. J., Lyu, J. F., and Shim, J. S. (2020) Histone Acetyltransferase (HAT) P300/CBP Inhibitors Induce Synthetic Lethality in PTEN-Deficient Colorectal Cancer Cells through Destabilizing AKT. Int J Biol Sci 16, 1774-1784
6. Lyu, J. F., Yang, E. J., and Shim, J. S. (2019) Cholesterol Trafficking: An Emerging Therapeutic Target for Angiogenesis and Cancer. Cells 8, E389
7. Zhang, B. Y., Lyu, J. F., Liu, Y. F., Wu, C. J., Yang, E. J., Pardeshi, L., Tan, K., Wong, K. H., Chen, Q., Xu, X. l., Deng, C. X., and Shim, J. S. (2018) BRCA1 Deficiency Sensitizes Breast Cancer Cells to Bromodomain and Extra-Terminal Domain (BET) Inhibition. Oncogene 37, 6341-6356
8. Wu, C. J., Lyu, J. F., Yang, E. J., Liu, Y. F., Zhang, B. Y., and Shim, J. S. (2018) Targeting AURKA-CDC25C Axis to Induce Synthetic Lethality in ARID1A-Deficient Colorectal Cancer Cells. Nat Commun 9, 3212
9. Lyu, J. F., Yang, E. J., Head, S., Ai, N., Zhang, B. Y., Wu, C. J., Li, R. J., Liu, Y. F., Chakravarty, H., Zhang, S. L., Tam, K. Y., Dang, Y. J., Kwon, H. J., Ge, W., Liu, J. O., and Shim, J. S. (2018) Astemizole Inhibits mTOR Signaling and Angiogenesis by Blocking Cholesterol Trafficking. Int J Biol Sci 14, 1175-1185
10. Liu, Y., Yang, E. J., Zhang, B. Y., Miao, Z. Q., Wu, C. J., Lyu, J. F., Tan, K., Poon, T. C. W., and Shim, J. S. (2018) PTEN Deficiency Confers Colorectal Cancer Cell Resistance to Dual Inhibitors of FLT3 and Aurora kinase A. Cancer Lett 436, 28-37
11. Lyu, J. F., Yang, E. J., Head, S., Ai, N., Zhang, B. Y., Wu, C. J., Li, R. J., Liu, Y. F., Yang, C., Dang, Y. J., Kwon, H. J., Ge, W., Liu, J. O., and Shim, J. S. (2017) Pharmacological Blockade of Cholesterol Trafficking by Cepharanthine in Endothelial Cells Suppresses Angiogenesis and Tumor Growth. Cancer Lett 409, 91-103
12. Shim, J. S., Li, R. J., Bumpus, N., Head, S., Pasunooti, K. K., Yang, E. J., Lv, J. f., Shi, W., and Liu, J. O. (2016) Divergence of Antiangiogenic Activity and Hepatotoxicity of Different Stereoisomers of Itraconazole. Clin Cancer Res 22, 2709-2720
13. Du, B. W., and Shim, J. S. (2016) Targeting Epithelial–Mesenchymal Transition (Emt) to Overcome Drug Resistance in Cancer. Molecules 21, 965
14. Wang, G. L., Rajpurohit, S., Delaspre, F., Walker, S., White, D., Ceasrine, A., Kuruvilla, R., Li, R. j., Shim, J. S., Liu, J. O., Parsons, M., and Mumm, J. (2015) First Quantitative High-Throughput Screen in Zebrafish Identifies Novel Pathways for Increasing Pancreatic Β-Cell Mass. Elife 4, e08261
15. Shim, J. S., Li, R. J., Lv, J. F., Head, S., Yang, E. J., and Liu, J. O. (2015) Inhibition of Angiogenesis by Selective Estrogen Receptor Modulators through Blockade of Cholesterol Trafficking Rather Than Estrogen Receptor Antagonism. Cancer Lett 362, 106-115
16. Head, S. A., Shi, W., Zhao, L., Gorshkov, K., Pasunooti, K., Chen, Y., Deng, Z., Li, R. j., Shim, J. S., Tan, W., Hartung, T., Zhang, J., Zhao, Y., Colombini, M., and Liu, J. O. (2015) Antifungal Drug Itraconazole Targets Vdac1 to Modulate the Ampk/mTOR Signaling Axis in Endothelial Cells. Proceedings of the National Academy of Sciences 112, E7276-E7285
17. Wang, M. H., Shim, J. S., Li, R. J., Dang, Y. J., He, Q. L., Das, M., and Liu, J. O. (2014) Identification of an Old Antibiotic Clofoctol as a Novel Activator of Unfolded Protein Response Pathways and an Inhibitor of Prostate Cancer. Brit J Pharmacol 171, 4478-4489
18. Shim, J. S., and Liu, J. O. (2014) Recent Advances in Drug Repositioning for the Discovery of New Anticancer Drugs. Int J Biol Sci 10, 654-663
19. Kamiyama, H., Rauenzahn, S., Shim, J. S., Karikari, C. A., Feldmann, G., Hua, L., Kamiyama, M., Schuler, F. W., Lin, M. T., Beaty, R. M., Karanam, B., Liang, H., Mullendore, M. E., Mo, G., Hidalgo, M., Jaffee, E., Hruban, R. H., Jinnah, H. A., Roden, R. B., Jimeno, A., Liu, J. O., Maitra, A., and Eshleman, J. R. (2013) Personalized Chemotherapy Profiling Using Cancer Cell Lines from Selectable Mice. Clin Cancer Res 19, 1139-1146
20. Choi, S. M., Kim, Y., Shim, J. S., Park, J. T., Wang, R. H., Leach, S. D., Liu, J. O., Deng, C., Ye, Z., and Jang, Y. Y. (2013) Efficient Drug Screening and Gene Correction for Treating Liver Disease Using Patient-Specific Stem Cells. Hepatology 57, 2458-2468
21. Shim, J. S., Rao, R., Beebe, K., Neckers, L., Han, I., Nahta, R., and Liu, J. O. (2012) Selective Inhibition of HER2-Positive Breast Cancer Cells by the HIV Protease Inhibitor Nelfinavir. J Natl Cancer Inst 104, 1576-1590
22. Liu-Chittenden, Y., Huang, B., Shim, J. S., Chen, Q., Lee, S. J., Anders, R. A., Liu, J. O., and Pan, D. (2012) Genetic and Pharmacological Disruption of the TEAD-YAP Complex Suppresses the Oncogenic Activity of YAP. Genes Dev 26, 1300-1305
23. Rovira, M., Huang, W., Yusuff, S., Shim, J. S., Ferrante, A. A., Liu, J. O., and Parsons, M. J. (2011) Chemical Screen Identifies FDA-Approved Drugs and Target Pathways That Induce Precocious Pancreatic Endocrine Differentiation. Proc Natl Acad Sci U S A 108, 19264-19269
24. Platz, E. A., Yegnasubramanian, S., Liu, J. O., Chong, C. R., Shim, J. S., Kenfield, S. A., Stampfer, M. J., Willett, W. C., Giovannucci, E., and Nelson, W. G. (2011) A Novel Two-Stage, Transdisciplinary Study Identifies Digoxin as a Possible Drug for Prostate Cancer Treatment. Cancer Discov 1, 68-77
25. Shim, J. S., Matsui, Y., Bhat, S., Nacev, B. A., Xu, J., Bhang, H. E., Dhara, S., Han, K. C., Chong, C. R., Pomper, M. G., So, A., and Liu, J. O. (2010) Effect of Nitroxoline on Angiogenesis and Growth of Human Bladder Cancer. J Natl Cancer Inst 102, 1855-1873
26. Shim, J. S., Lee, J., Park, H. J., Park, S. J., and Kwon, H. J. (2004) A New Curcumin Derivative, HBC, Interferes with the Cell Cycle Progression of Colon Cancer Cells Via Antagonization of the Ca2+/Calmodulin Function. Chem Biol 11, 1455-1463
27. Shim, J. S., Lee, H. S., Shin, J., and Kwon, H. J. (2004) Psammaplin A, a Marine Natural Product, Inhibits Aminopeptidase N and Suppresses Angiogenesis in Vitro. Cancer Lett 203, 163-169
28. Shim, J. S., and Kwon, H. J. (2004) Chemical Genetics for Therapeutic Target Mining. Expert Opin Ther Targets 8, 653-661
29. Shim, J. S., Kim, D. H., and Kwon, H. J. (2004) Plakoglobin Is a New Target Gene of Histone Deacetylase in Human Fibrosarcoma HT1080 Cells. Oncogene 23, 1704-1711
30. Shim, J. S., Kim, J. H., Cho, H. Y., Yum, Y. N., Kim, S. H., Park, H. J., Shim, B. S., Choi, S. H., and Kwon, H. J. (2003) Irreversible Inhibition of CD13/aminopeptidase N by the Antiangiogenic Agent Curcumin. Chem Biol 10, 695-704

• International patent: WO/2010/042163 – Quinoline compounds as inhibitors of angiogenesis, human methionine aminopeptidase, and SIRT1, and methods of treating disorders. Liu JO, Shim JS, Chong CR, and Bhat S. 04/15/2010
• Korea patent: 1006410760000 – A novel aminopeptidase N Inhibitor. Kwon HJ, Lee J and Shim JS. 10/25/2006
• Korea patent: 1006046970000 – A novel calmodulin antagonist and an immunosuppressive agent comprising thereof. Kwon HJ, Shim JS and Lee J. 07/19/2006
• International patent: WO/2003/105751 – Novel curcumin derivatives. Kwon HJ, Shim JS, Kim JH, Choi SH, Shin JH and Rho JR. 12/24/2003