TY - JOUR
T1 - Somatic mutation of the cohesin complex subunit confers therapeutic vulnerabilities in cancer
AU - Liu, Yunhua
AU - Xu, Hanchen
AU - Van Der Jeught, Kevin
AU - Li, Yujing
AU - Liu, Sheng
AU - Zhang, Lu
AU - Fang, Yuanzhang
AU - Zhang, Xinna
AU - Radovich, Milan
AU - Schneider, Bryan P.
AU - He, Xiaoming
AU - Huang, Cheng
AU - Zhang, Chi
AU - Wan, Jun
AU - Ji, Guang
AU - Lu, Xiongbin
N1 - Publisher Copyright:
© 2018 American Society for Clinical Investigation. All rights reserved.
PY - 2018/7/2
Y1 - 2018/7/2
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI98727
DO - 10.1172/JCI98727
M3 - Article
C2 - 29649003
AN - SCOPUS:85049834063
SN - 0021-9738
VL - 128
SP - 2951
EP - 2965
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 7
ER -