期刊
MOLECULAR CANCER THERAPEUTICS
卷 19, 期 8, 页码 1727-1735出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-19-0977
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资金
- NIH [P50 CA217685, P50 CA098258, R35 CA209904, CA016672]
- American Cancer Society Research Professor Award
- BlantonDavis Ovarian Cancer Research Program
- RGK Foundation
- Frank McGraw Memorial Chair in Cancer Research
- Liz Tilberis Early Career Award
- OCRF
- Ovarian Cancer Research Alliance (OCRA) [FP00006137]
- Gulf Coast Consortia, on the Computational Cancer Biology Training Program (CPRIT) [RP170593]
- NIH through theOvarian Spore Career Enhancement Program
- NCI [FP00000019]
- Ovarian Cancer Research Fund Alliance
- Foundation for Women's Cancer
- Texas Center for Cancer Nanomedicine
- Cancer Prevention and Research Institute of Texas [RP101502, RP101489]
XPO1 inhibitors have shown promise in cancer treatment, but mechanisms of resistance to these drugs are not well understood. In this study, we established selective inhibitors of nuclear export (SINE)-resistant ovarian cancer cell lines from in vivo mouse tumors and determined the mechanisms of adaptive XPO1 inhibitor resistance using protein and genomic arrays. Pathway analyses revealed upregulation of the NRG1/ERBB3 pathway in SINE-resistant cells. Depletion of ERBB3 using siRNAs restored the antitumor effect of SLNE in vitro and in vivo. Furthermore, exogenous NRG1 decreased the antitumor effect of SINE in ovarian cancer cell lines with high ERBB3 expression, but not in those with low expression. These results suggest that NRG1 and ERBB3 expression is a potential biomarker of response to SINE treatment. The antitumor effect of SINE was reduced by exogenous NRG1 in an ERBB3-dependent manner. These findings suggest that NRG1 and ERBB3 are effective biomarkers that should be evaluated in future clinical trials and are relevant therapeutic targets for the treatment of SINE-resistant cancers.
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