Somatic mutation of the cohesin complex subunit confers therapeutic vulnerabilities in cancer

Yunhua Liu, Hanchen Xu, Kevin Van Der Jeught, Yujing Li, Sheng Liu, Lu Zhang, Yuanzhang Fang, Xinna Zhang, Milan Radovich, Bryan Schneider, Xiaoming He, Cheng Huang, Chi Zhang, Jun Wan, Guang Ji, Xiongbin Lu

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

A synthetic lethality–based strategy has been developed to identify therapeutic targets in cancer harboring tumor-suppressor gene mutations, as exemplified by the effectiveness of poly ADP-ribose polymerase (PARP) inhibitors in BRCA1/2-mutated tumors. However, many synthetic lethal interactors are less reliable due to the fact that such genes usually do not perform fundamental or indispensable functions in the cell. Here, we developed an approach to identifying the “essential lethality” arising from these mutated/deleted essential genes, which are largely tolerated in cancer cells due to genetic redundancy. We uncovered the cohesion subunit SA1 as a putative synthetic-essential target in cancers carrying inactivating mutations of its paralog, SA2. In SA2-deficient Ewing sarcoma and bladder cancer, further depletion of SA1 profoundly and specifically suppressed cancer cell proliferation, survival, and tumorigenic potential. Mechanistically, inhibition of SA1 in the SA2-mutated cells led to premature chromatid separation, dramatic extension of mitotic duration, and consequently, lethal failure of cell division. More importantly, depletion of SA1 rendered those SA2-mutated cells more susceptible to DNA damage, especially double-strand breaks (DSBs), due to reduced functionality of DNA repair. Furthermore, inhibition of SA1 sensitized the SA2-deficient cancer cells to PARP inhibitors in vitro and in vivo, providing a potential therapeutic strategy for patients with SA2-deficient tumors.

Original languageEnglish (US)
Pages (from-to)2951-2965
Number of pages15
JournalJournal of Clinical Investigation
Volume128
Issue number7
DOIs
StatePublished - Jul 2 2018

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Mutation
Neoplasms
Therapeutics
Genetic Suppression
Chromatids
Ewing's Sarcoma
Essential Genes
cohesins
Tumor Suppressor Genes
Urinary Bladder Neoplasms
DNA Repair
Cell Division
DNA Damage
Cell Survival
Cell Proliferation
Genes
Poly(ADP-ribose) Polymerase Inhibitors

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Liu, Y., Xu, H., Van Der Jeught, K., Li, Y., Liu, S., Zhang, L., ... Lu, X. (2018). Somatic mutation of the cohesin complex subunit confers therapeutic vulnerabilities in cancer. Journal of Clinical Investigation, 128(7), 2951-2965. https://doi.org/10.1172/JCI98727

Somatic mutation of the cohesin complex subunit confers therapeutic vulnerabilities in cancer. / Liu, Yunhua; Xu, Hanchen; Van Der Jeught, Kevin; Li, Yujing; Liu, Sheng; Zhang, Lu; Fang, Yuanzhang; Zhang, Xinna; Radovich, Milan; Schneider, Bryan; He, Xiaoming; Huang, Cheng; Zhang, Chi; Wan, Jun; Ji, Guang; Lu, Xiongbin.

In: Journal of Clinical Investigation, Vol. 128, No. 7, 02.07.2018, p. 2951-2965.

Research output: Contribution to journalArticle

Liu, Y, Xu, H, Van Der Jeught, K, Li, Y, Liu, S, Zhang, L, Fang, Y, Zhang, X, Radovich, M, Schneider, B, He, X, Huang, C, Zhang, C, Wan, J, Ji, G & Lu, X 2018, 'Somatic mutation of the cohesin complex subunit confers therapeutic vulnerabilities in cancer', Journal of Clinical Investigation, vol. 128, no. 7, pp. 2951-2965. https://doi.org/10.1172/JCI98727
Liu, Yunhua ; Xu, Hanchen ; Van Der Jeught, Kevin ; Li, Yujing ; Liu, Sheng ; Zhang, Lu ; Fang, Yuanzhang ; Zhang, Xinna ; Radovich, Milan ; Schneider, Bryan ; He, Xiaoming ; Huang, Cheng ; Zhang, Chi ; Wan, Jun ; Ji, Guang ; Lu, Xiongbin. / Somatic mutation of the cohesin complex subunit confers therapeutic vulnerabilities in cancer. In: Journal of Clinical Investigation. 2018 ; Vol. 128, No. 7. pp. 2951-2965.
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