Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 4443-4454 |
| Number of pages | 12 |
| Journal | Oncogene |
| Volume | 37 |
| Issue number | 32 |
| DOIs | |
| Publication status | Published - 2018 Aug 9 |
Bibliographical note
Funding Information:Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
Funding Information:
Acknowledgements 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).
Publisher Copyright:
© 2018, Macmillan Publishers Limited, part of Springer Nature.
All Science Journal Classification (ASJC) codes
- Molecular Biology
- Genetics
- Cancer Research
