NRG1/ERBB3 pathway activation induces acquired resistance to XPO1 inhibitors

Takahito M. Miyake, Sunila Pradeep, Emine Bayraktar, Elaine Stur, Katelyn F. Handley, Sherry Y. Wu, Cristian Rodriguez-Aguayo, Ju Seog Lee, Gabriel Lopez-Berestein, Robert L. Coleman, Anil K. Sood

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1727-1735
Number of pages9
JournalMolecular cancer therapeutics
Volume19
Issue number8
DOIs
StatePublished - Aug 1 2020

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

MD Anderson CCSG core facilities

  • Flow Cytometry and Cellular Imaging Facility
  • Research Animal Support Facility
  • Advanced Technology Genomics Core
  • Cytogenetics and Cell Authentication Core
  • Functional Proteomics Reverse Phase Protein Array Core
  • Bioinformatics Shared Resource

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