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Histone Deacetylase 3 Inhibition Overcomes BIM Deletion Polymorphism-Mediated Osimertinib Resistance in EGFR-Mutant Lung Cancer.

Publication ,  Journal Article
Tanimoto, A; Takeuchi, S; Arai, S; Fukuda, K; Yamada, T; Roca, X; Ong, ST; Yano, S
Published in: Clin Cancer Res
June 15, 2017

Purpose: The BIM deletion polymorphism is associated with apoptosis resistance to EGFR tyrosine kinase inhibitors (EGFR-TKI), such as gefitinib and erlotinib, in non-small cell lung cancer (NSCLC) harboring EGFR mutations. Here, we investigated whether the BIM deletion polymorphism contributes to resistance against osimertinib, a third-generation EGFR-TKI. In addition, we determined the efficacy of a histone deacetylase (HDAC) inhibitor, vorinostat, against this form of resistance and elucidated the underlying mechanism.Experimental Design: We used EGFR-mutated NSCLC cell lines, which were either heterozygous or homozygous for the BIM deletion polymorphism, to evaluate the effect of osimertinib in vitro and in vivo Protein expression was examined by Western blotting. Alternative splicing of BIM mRNA was analyzed by RT-PCR.Results:EGFR-mutated NSCLC cell lines with the BIM deletion polymorphism exhibited apoptosis resistance to osimertinib in a polymorphism dosage-dependent manner, and this resistance was overcome by combined use with vorinostat. Experiments with homozygous BIM deletion-positive cells revealed that vorinostat affected the alternative splicing of BIM mRNA in the deletion allele, increased the expression of active BIM protein, and thereby induced apoptosis in osimertinib-treated cells. These effects were mediated predominantly by HDAC3 inhibition. In xenograft models, combined use of vorinostat with osimertinib could regress tumors in EGFR-mutated NSCLC cells homozygous for the BIM deletion polymorphism. Moreover, this combination could induce apoptosis even when tumor cells acquired EGFR-T790M mutations.Conclusions: These findings indicate the importance of developing HDAC3-selective inhibitors, and their combined use with osimertinib, for treating EGFR-mutated lung cancers carrying the BIM deletion polymorphism. Clin Cancer Res; 23(12); 3139-49. ©2016 AACR.

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Published In

Clin Cancer Res

DOI

EISSN

1557-3265

Publication Date

June 15, 2017

Volume

23

Issue

12

Start / End Page

3139 / 3149

Location

United States

Related Subject Headings

  • Vorinostat
  • Sequence Deletion
  • Protein Kinase Inhibitors
  • Piperazines
  • Oncology & Carcinogenesis
  • Hydroxamic Acids
  • Humans
  • Histone Deacetylases
  • Histone Deacetylase Inhibitors
  • ErbB Receptors
 

Citation

APA
Chicago
ICMJE
MLA
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Tanimoto, A., Takeuchi, S., Arai, S., Fukuda, K., Yamada, T., Roca, X., … Yano, S. (2017). Histone Deacetylase 3 Inhibition Overcomes BIM Deletion Polymorphism-Mediated Osimertinib Resistance in EGFR-Mutant Lung Cancer. Clin Cancer Res, 23(12), 3139–3149. https://doi.org/10.1158/1078-0432.CCR-16-2271
Tanimoto, Azusa, Shinji Takeuchi, Sachiko Arai, Koji Fukuda, Tadaaki Yamada, Xavier Roca, S Tiong Ong, and Seiji Yano. “Histone Deacetylase 3 Inhibition Overcomes BIM Deletion Polymorphism-Mediated Osimertinib Resistance in EGFR-Mutant Lung Cancer.Clin Cancer Res 23, no. 12 (June 15, 2017): 3139–49. https://doi.org/10.1158/1078-0432.CCR-16-2271.
Tanimoto A, Takeuchi S, Arai S, Fukuda K, Yamada T, Roca X, et al. Histone Deacetylase 3 Inhibition Overcomes BIM Deletion Polymorphism-Mediated Osimertinib Resistance in EGFR-Mutant Lung Cancer. Clin Cancer Res. 2017 Jun 15;23(12):3139–49.
Tanimoto, Azusa, et al. “Histone Deacetylase 3 Inhibition Overcomes BIM Deletion Polymorphism-Mediated Osimertinib Resistance in EGFR-Mutant Lung Cancer.Clin Cancer Res, vol. 23, no. 12, June 2017, pp. 3139–49. Pubmed, doi:10.1158/1078-0432.CCR-16-2271.
Tanimoto A, Takeuchi S, Arai S, Fukuda K, Yamada T, Roca X, Ong ST, Yano S. Histone Deacetylase 3 Inhibition Overcomes BIM Deletion Polymorphism-Mediated Osimertinib Resistance in EGFR-Mutant Lung Cancer. Clin Cancer Res. 2017 Jun 15;23(12):3139–3149.

Published In

Clin Cancer Res

DOI

EISSN

1557-3265

Publication Date

June 15, 2017

Volume

23

Issue

12

Start / End Page

3139 / 3149

Location

United States

Related Subject Headings

  • Vorinostat
  • Sequence Deletion
  • Protein Kinase Inhibitors
  • Piperazines
  • Oncology & Carcinogenesis
  • Hydroxamic Acids
  • Humans
  • Histone Deacetylases
  • Histone Deacetylase Inhibitors
  • ErbB Receptors