@article{35105cd7c5854ea0981df24896914c01,
title = "NRG1/ERBB3 pathway activation induces acquired resistance to XPO1 inhibitors",
abstract = "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 SINE 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.",
author = "Miyake, {Takahito M.} and Sunila Pradeep and Emine Bayraktar and Elaine Stur and Handley, {Katelyn F.} and Wu, {Sherry Y.} and Cristian Rodriguez-Aguayo and Lee, {Ju Seog} and Gabriel Lopez-Berestein and Coleman, {Robert L.} and Sood, {Anil K.}",
note = "Funding Information: R.L. Coleman is a consultant at Clovis, Roche, AstraZeneca, Tesaro/GSK, Abbvie, Mateo, Agenus, Genmab, Iovance, Aravive, and reports receiving a commercial research grant from Merck, AstraZeneca, Clovis, Abbvie, and Johnson and Johnson. A.K. Sood is a consultant at Merck and Kiyatec, and reports receiving a commercial research grant from M-Trap, has ownership interest (including patents) in BioPath. No potential conflicts of interest were disclosed by the other authors. Funding Information: A.K. Sood is supported by the NIH (P50 CA217685, P50 CA098258, R35 CA209904), the American Cancer Society Research Professor Award, the Blanton-Davis Ovarian Cancer Research Program, the RGK Foundation, and the Frank McGraw Memorial Chair in Cancer Research. S. Pradeep is supported by the Liz Tilberis Early Career Award and OCRF. E. Stur is supported by Ovarian Cancer Research Alliance (OCRA number FP00006137). K. F. Handley is supported by a training fellowship from the Gulf Coast Consortia, on the Computational Cancer Biology Training Program (CPRIT grant no. RP170593). C. Rodriguez-Aguayo was supported by the NIH through the Ovarian Spore Career Enhancement Program, and the NCI grant FP00000019. S. Wu was supported by Ovarian Cancer Research Fund Alliance, Foundation for Women{\textquoteright}s Cancer, Texas Center for Cancer Nanomedicine, and Cancer Prevention and Research Institute of Texas training grants (RP101502 and RP101489, respectively). The MD Anderson Research Core Facilities are funded by NIH grant CA016672. Publisher Copyright: {\textcopyright} 2020 American Association for Cancer Research.",
year = "2020",
month = aug,
day = "1",
doi = "10.1158/1535-7163.MCT-19-0977",
language = "English (US)",
volume = "19",
pages = "1727--1735",
journal = "Molecular cancer therapeutics",
issn = "1535-7163",
publisher = "American Association for Cancer Research Inc.",
number = "8",
}