Prof Joong Sup SHIM

[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. Zhang X, Wang Z, He Y, Wang K, Xiang C, Liu Y, Song Y, Li A, Wang Z, Yu Y, Peng W, Liu S*, Shim JS*, Wu C*. ARID1A loss enhances sensitivity to c-MET inhibition by dual targeting of GPX4 and iron homeostasis, inducing ferroptosis. Cell Death Differ. 2025; doi: 10.1038/s41418-025-01510-x.
2. Pu Y, Wang Z, Tao S, Yang EJ, Wu S, Ren G, Chen LJ, Zhang X, Tan K, Dang Y, Shim JS*. Microtubule dynamics is a therapeutic vulnerability in VHL-deficient renal cell carcinoma. Int J Biol Sci. 2025; 21(7):3286-3305.
3. He W, Chen C, Cai R, Zheng J, Yao M, Shim JS, Kwok HF, Yao X, Fang L, Chen L. Bifunctional compounds for targeted degradation of carbonic anhydrase IX through integrin-facilitated lysosome degradation. J Biol Chem. 2025; 301(5):108482.
4. Tao S, Pu Y, Yang EJ, Ren G, Shi C, Chen LJ, Chen L, Shim JS*. Inhibition of GSK3β is synthetic lethal with FHIT loss in lung cancer via blocking homologous recombination repair. Exp Mol Med. 2025; 57(1):167-183.
5. Ren G, Chen J, Pu Y, Yang EJ, Tao S, Mou PK, Chen LJ, Zhu W, Chan KL, Luo G, Deng C, Shim JS*. BET inhibition induces synthetic lethality in PTEN deficient colorectal cancers via dual action on p21CIP1/WAF1. Int J Biol Sci. 2024; 20(6):1978-1991
6. Ren G, Yang EJ, Tao S, Mou PK, Pu Y, Chen LJ, Shim JS*. MDM2 inhibition is synthetic lethal with PTEN loss in colorectal cancer cells via the p53-dependent mechanism. Int J Biol Sci. 2023; 19(11):3544-3557
7. Tao S, Yang EJ, Zong G, Mou PK, Ren G, Pu Y, Chen L, Kwon HJ, Zhou J, Hu Z, Khosravi A, Zhang Q, Du Y, Shi WQ, Shim JS*. ER translocon inhibitor ipomoeassin F inhibits triple-negative breast cancer growth via blocking ER molecular chaperones. Int J Biol Sci. 2023; 19(13):4020-4035
8. Shu X, Li J, Chan UI, Su SM, Shi C, Zhang X, An T, Xu J, Mo L, Liu J, Wang Y, Li X, Deng M, Lei JH, Wang C, Tian H, Heng S, Shim JS, Zhang X, Dai Y, Yao Z, Kuang X, Lin Y, Deng CX, Xu X. BRCA1 insufficiency induces a hypersialylated acidic tumor microenvironment that promotes metastasis and immunotherapy resistance. Cancer Res. 2023; 83(15):2614-2633
9. Wang X, Huang J, Liu F, Yu Q, Wang R, Wang J, Zhu Z, Yu J, Hou J, Shim JS, Jiang W, Li Z, Zhang Y, Dang Y. Aurora A kinase inhibition elevates PD-L1 expression and compromises its anti-tumor efficacy. J Clin Invest. 2023; e161929.
10. Xiong Y, Ke R, Zhang Q, Lan W, Yuan W, Chan KNI, Roussel T, Jiang Y, Wu J, Liu S, Wong AST, Shim JS, Zhang X, Xie R, Dusetti N, Iovanna J, Habib N, Peng L, Lee LTO. Small Activating RNA Modulation of the G Protein-Coupled Receptor for Cancer Treatment. Adv Sci. 2022; 9(26):e2200562.
11. Shi C, Tao S, Ren G, Yang EJ, Shu X, Mou PK, Liu Y, Dang Y, Xu X, Shim JS*. Aurora kinase A inhibition induces synthetic lethality in SMAD4-deficient colorectal cancer cells via spindle assembly checkpoint activation. Oncogene. 2022; doi: 10.1038/s41388-022-02293-y.
12. Zhang L, Chen C, Fu J, Lilley B, Berlinicke C, Hansen B, Ding D, Wang G, Wang T, Shou D, Ye Y, Mulligan T, Emmerich K, Saxena MT, Hall KR, Sharrock AV, Brandon C, Park H, Kam TI, Dawson VL, Dawson TM, Shim JS, Hanes J, Ji H, Liu JO, Qian J, Ackerley DF, Rohrer B, Zack DJ, Mumm JS. Large-scale phenotypic drug screen identifies neuroprotectants in zebrafish and mouse models of retinitis pigmentosa. eLife. 2021; 10:e57245.
13. Mou PK, Yang EJ, Shi C, Ren G, Tao S, Shim JS*. Aurora kinase A, a synthetic lethal target for precision cancer medicine. Exp Mol Med, 2021; 53(5):835-847.
14. Ding RB, Chen P, Rajendran BK, Lyu X, Wang H, Bao J, Zeng J, Hao W, Sun H, Wong AH, Valecha MV, Yang EJ, Su SM, Choi TK, Liu S, Chan KI, Yang LL, Wu J, Miao K, Chen Q, Shim JS, Xu X, Deng CX. Molecular landscape and subtype-specific therapeutic response of nasopharyngeal carcinoma revealed by integrative pharmacogenomics. Nat Commun, 2021; 12(1):3046.
15. Shi C, Yang EJ, Liu Y, Mou PK, Ren G, Shim JS*. 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, 2020; DOI: 10.1038/s41388-020-01580-w.
16. Hwang HY, Shim JS, Kim D, Kwon HJ. Antidepressant Drug Sertraline Modulates AMPK-MTOR Signaling-Mediated Autophagy via Targeting Mitochondrial VDAC1 Protein. Autophagy, 2020; DOI: 10.1080/15548627.2020.1841953.
17. Lyu J, Yang EJ, Zhang B, Wu C, Pardeshi L, Shi C, Mou PK, Liu Y, Tan K, Shim JS*. Synthetic lethality of RB1 and aurora A is driven by stathmin-mediated disruption of microtubule dynamics. Nat Commun, 2020; 11(1):5105.
18. Liu Y, Yang EJ, Shi C, Mou PK, Zhang B, Wu C, Lyu J, Shim JS*. Histone acetyltransferase (HAT) p300/CBP inhibitors induce synthetic lethality in PTEN-deficient colorectal cancer cells through destabilizing AKT. Int J Biol Sci, 2020; 16(11):1774-1784.
19. Zhang B, Lyu J, Yang EJ, Liu Y, Wu C, Pardeshi L, Tan K, Chen Q, Xu X, Deng CX, Shim JS*. Class I histone deacetylase inhibition is synthetic lethal with BRCA1 deficiency in breast cancer cells. Acta Pharm Sin B, 2020; 10(4):615-627.
20. Lyu J, Yang EJ, Shim JS*. Cholesterol trafficking: an emerging therapeutic target for angiogenesis and cancer. Cells, 2019; 8(5), pii: E389.
21. Wu C, Lyu J, Yang EJ, Liu Y, Zhang B, Shim JS*. Targeting AURKA-CDC25C axis to induce synthetic lethality in ARID1A-deficient colorectal cancer cells. Nat Commun, 2018; 9(1):3212.
22. Liu Y, Yang EJ, Zhang B, Miao Z, Wu C, Lyu J, Tan K, Wong KH, Poon TCW, Shim JS*. PTEN deficiency confers colorectal cancer cell resistance to dual inhibitors of FLT3 and aurora A kinases. Cancer Lett, 2018; 436:28-37.
23. Zhang B, Lyu J, Liu Y, Wu C, Yang EJ, Pardeshi L, Tan K, Wong KH, Chen Q, Xu X, Deng CX, Shim JS*. BRCA1 deficiency sensitizes breast cancer cells to bromodomain and extra-terminal domain (BET) inhibition. Oncogene, 2018; 37(49):6341-6356.
24. Lyu J, Yang EJ, Head SA, Ai N, Zhang B, Wu C, Li RJ, Liu Y, Chakravarty H, Zhang S, Tam KY, Dang Y, Kwon HJ, Ge W, Liu JO, Shim JS*. Astemizole inhibits mTOR signaling and angiogenesis by blocking cholesterol trafficking. Int J Biol Sci, 2018; 14(10):1175-1185.
25. Lyu J, Yang EJ, Head SA, Ai N, Zhang B, Wu C, Li RJ, Liu Y, Yang C, Dang Y, Kwon HJ, Ge W, Liu JO, Shim JS*. Pharmacological blockade of cholesterol trafficking by cepharanthine in endothelial cells suppresses angiogenesis and tumor growth. Cancer Lett, 2017; 409:91-103.
26. Du B and Shim JS*. Targeting epithelial-mesenchymal transition (EMT) to overcome drug resistance in cancer. Molecules, 2016; 21(7):E965.
27. Shim JS, Li RJ, Bumpus NN, Head SA, Kumar K, Yang EJ, Lv J, Shi W, Liu JO. Divergence of anti-angiogenic activity and hepatotoxicity of different stereoisomers of itraconazole. Clin Cancer Res, 2016; 22(11):2709-20.
28. Head SA, Shi WQ, Zhao L, Gorshkov K, Pasunooti KK, Chen Y, Deng Z, Li RJ, Shim JS, Tan W, Hartung T, Zhang J, Zhao Y, Colombini M, Liu JO. The antifungal drug itraconazole targets VDAC1 to modulate the AMPK/mTOR signaling axis in endothelial cells. Proc Natl Acad Sci, 2015; 112(52):E7276-85.
29. Wang G, Rajpurohit SK, Delaspre F, Walker SL, White DT, Ceasrine A, Kuruvilla R, Li RJ, Shim JS, Liu JO, Parsons MJ, Mumm JS. First quantitative high-throughput screen in zebrafish identifies novel pathways for increasing pancreatic β-cell mass. eLife, 2015; 10.7554/eLife.08261.
30. Shim JS, Rao R, Beebe K, Neckers L, Han I, Nahta R and Liu JO. Selective inhibition of HER2-positive breast cancer cells by the HIV protease inhibitor nelfinavir. J Natl Cancer Inst, 2012; 104(20):1576-90.

• 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