Oops, you're using an old version of your browser so some of the features on this page may not be displaying properly.

MINIMAL Requirements: Google Chrome 24+Mozilla Firefox 20+Internet Explorer 11Opera 15–18Apple Safari 7SeaMonkey 2.15-2.23

Poster Display session 1

1294 - Hsp90 inhibitors enhance the antitumoral effect of osimertinib and overcome osimertinib resistance in non-small-cell cell lung cancer cell models

Date

28 Sep 2019

Session

Poster Display session 1

Presenters

Jordi Codony-Servat

Citation

Annals of Oncology (2019) 30 (suppl_5): v1-v24. 10.1093/annonc/mdz238

Authors

J. Codony-Servat1, C. Codony-Servat1, S. Viteri2, M. Ito1, I. Chaib3, J. Bracht1, M.A. Molina-Vila1, N. Karachaliou4, R. Rosell3

Author affiliations

  • 1 Laboratory Of Oncology - Pangaea Oncology, Quirón-Dexeus University Institute, 08028 - Barcelona/ES
  • 2 Oncology, Quirón-Dexeus University Institute, 08028 - Barcelona/ES
  • 3 Laboratory Of Cellular And Molecular Biology, Institut for Healh Sciences Germans Trias i Pujol, 08916 - Badalona/ES
  • 4 Rd-doo Clinical Oncology, Merck KgaA, Darmstadt/DE
More

Resources

Abstract 1294

Background

The epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) osimertinib improves therapy for non-small cell lung cancer (NSCLC) patients who possess EGR mutations. However, invariable acquired resistance appears due to several molecular mechanisms. Hsp90 protein clients are involved in these processes.

Methods

Cell viability and colony formation assays were performed in PC9, H1975 and PC9-derived osimertinib-resistant NSCLC cell lines tested with osimertinib plus hsp90 inhibitors, luminespib or ganetespib. To analyze the mechanism of action of these compounds and its combination, western blot analysis was carried out to study the protein expression and activation.

Results

In our laboratory five osimertinib-resistant cell lines were generated from PC9 NSCLC cell line and overexpression or activation of several proteins, such as, AXL, Yap, bcl2, Akt, Stat3 and IGF-1R were detected. Hsp90 inhibitors, Ganetespib and Luminespib, inhibited cell viability and colony formation in H1975, PC9 and PC9-derived osimertinib-resistant cell lines, and the combination of these inhibitors with osimertinib achieved enhanced cell viability reduction. Luminespib downregulated the expression of several proteins involved in osimertinib-resistance and the combination of this compound plus osimertinib caused an important decrease of expression in several of these proteins, such as, Stat3, Yap, Akt, EGFR and Met. In addition, osimertinib activated the phosphorylation of several membrane receptors and downstream molecules, such as, Met, Yap, Stat3, Akt and Src, and its activation was partially inhibited by Luminespib.

Conclusions

We conclude that hsp90 inhibitors and osimertinib exhibit good efficiency in inhibiting cell viability and colony formation, while at the same time, inhibiting expression and activation of proteins involved in osimertinib-resistance. Our preclinical study shows that the combination of hsp90 inhibitors and osimertinib may represent an effective strategy for NSCLC patients with resistance to osimertinib treatment.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Pangaea Oncology.

Funding

Pangaea Oncology.

Disclosure

All authors have declared no conflicts of interest.

This site uses cookies. Some of these cookies are essential, while others help us improve your experience by providing insights into how the site is being used.

For more detailed information on the cookies we use, please check our Privacy Policy.

Customise settings