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Pharmacologically targetable vulnerability in prostate cancer carrying RB1-SUCLA2 deletion

Abstract

RB1 gene is often homozygously deleted or mutated in prostate adenocarcinomas following acquirement of castration resistance and/or metastatic ability. We found that SUCLA2 gene is frequently involved in the deletion of the RB1 gene region in advanced prostate cancer. SUCLA2 constitutes the β-subunit of succinate CoA ligase heterodimer that reversibly converts succinyl CoA into succinate. We sought the possibility that deletion of SUCLA2 gives rise to a metabolic vulnerability that could be targeted therapeutically. We found a significant metabolic shift in SUCLA2-deleted prostate cancer cells, including lower mitochondrial respiratory activity. By screening a number of libraries for compounds that induce cell death selectively in SUCLA2-deficient prostate cancer cells, we identified thymoquinone (2-isopropyl-5-methylbenzo-1,4-quinone) and PMA (phorbol-12-myristate-13-acetate) from a natural compound library. These findings indicate that the metabolic vulnerability in SUCLA2-deficient prostate cancer cells is pharmacologically targetable.

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Fig. 1: RB1 and SUCLA2 deletion in prostate cancer.
Fig. 2: Metabolomic features of SUCLA2-deleted prostate cancer cells.
Fig. 3: Metabolic characteristics of SUCLA2-deleted prostate cancer cells.
Fig. 4: Screening of small molecules that selectively kill SUCLA2-deleted prostate cancer cells.
Fig. 5: Thymoquinone suppresses SUCLA2-deficient prostate cancer.
Fig. 6: TQ induces cell death in SUCLA2-deficient cells irrespective of the RB1 status.

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Acknowledgements

We thank Drs. Y. Hirota and S. Tsutsumi for the substantial contribution to the initiation of work, Dr. A. Mizokami for helpful discussion, and Dr. Y. Watanabe for suggestion on research direction. This study was supported by Funding Program for Next Generation World-Leading Researchers (LS049) from cabinet office of Japan, Grant-in-Aid for Scientific Research (17H03576, 17K19586 and 19K22555 to CT, and 17K14992 and 20K07612 to SK) from MEXT, Project for Cancer Research and Therapeutic (P-CREATE) (19cm0106164h0001) from Japan Agency for Medical Research and Development (AMED), and TaNeDS (C1010568) and a collaborative research fund (C1010818) from Daiichi-Sankyo Co. Ltd. SK was supported by a Senior Principal Research Fellowship from the National Health & Medical Research Council of Australia (GNT 1103006).

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SK conceived the idea, designed and performed experiments, analyzed data, and wrote the paper. PL designed and performed experiments, analyzed data, and wrote the paper. NN provided technical help. YW helped design the experiments. SK provided intellectual input, edited and critically revised the paper. TS performed metabolomic experiments and analyzed data. CT conceived the idea, helped design the experiments, obtained funding for the study, and helped draft and critically revised the paper.

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Correspondence to Susumu Kohno or Chiaki Takahashi.

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Kohno, S., Linn, P., Nagatani, N. et al. Pharmacologically targetable vulnerability in prostate cancer carrying RB1-SUCLA2 deletion. Oncogene 39, 5690–5707 (2020). https://doi.org/10.1038/s41388-020-1381-6

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