Gene mutations play critical roles during cancer development and progression, and therefore represent targets for precision medicine. Here we recapitulated the pharmacogenomic data to delineate novel candidates for actionable mutations and therapeutic target drugs. As a proof-of-concept, we demonstrated that the loss-of-function of SULF2 by mutation (N491K) or inhibition enhanced sorafenib sensitivity in liver cancer cells and in vivo mouse models. This effect was mediated by deregulation of EGFR signaling and downstream expression of LCN2. We also report that the liver cancer patients non-responding to sorafenib treatment exhibit higher expression of SULF2 and LCN2. In conclusion, we suggest that SULF2 plays a key role in sorafenib susceptibility and resistance in liver cancer via deregulation of LCN2. Diagnostic or therapeutic targeting of SULF2 (e.g., OKN-007) and/or LCN2 can be a novel precision strategy for sorafenib treatment in cancer patients.
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This work was supported by grants from the Korea Healthcare Technology R&D Project, Ministry of Health & Welfare (HI15C1551 and HI14C3392) and from the National Research Foundation of Korea (NRF) funded by the Korea government (MSIP) (NRF-2017M3A9B6061509, NRF-2017R1E1A1A01074733, and NRF-2015R1D1A4A01020022).
SY performed experiments. E-JL performed analysis. Both SY and E-JL wrote the manuscript that was edited by all co-authors. J-HC, H-HK, and HCK performed analysis. J-YI performed experiments. TC, DYK. M-HB, J-HK, YNP, and H-JW provided tissues and performed analysis. HGW contributed to overall study design and directed the study.
Conflict of interest
The authors declare that they have no conflict of interest.
These authors contributed equally: Sarah Yoon, Eun-Ju Lee.
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Yoon, S., Lee, EJ., Choi, JH. et al. Recapitulation of pharmacogenomic data reveals that invalidation of SULF2 enhance sorafenib susceptibility in liver cancer. Oncogene 37, 4443–4454 (2018). https://doi.org/10.1038/s41388-018-0291-3
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