Reversion of mesenchymal behaviour by AZD9291 (osimertinib) in EGFR mutant NSCLC cell lines resistant to first generation EGFR tyrosine kinase inhibitors

Date

10 Oct 2016

Session

Poster display

Presenters

Beatrice Savastano

Citation

Annals of Oncology (2016) 27 (6): 1-14. 10.1093/annonc/mdw362

Authors

B. Savastano, C.M. Della Corte, F. Papaccio, V. Giuseppe, G. Esposito, M. Fasano, M. Orditura, F. De Vita, F. Ciardiello, F. Morgillo

Author affiliations

  • Medicina Clinica Sperimentale Magrassi Lanzara, AOU Seconda Università degli Studi di Napoli (AOU-SUN), 80131 - Napoli/IT
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Background

Resistance to first-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs) is mainly mediated by the acquisition of the EGFR secondary mutation T790M and/or by the acquisition of a mesenchymal phenotype. We explored the occurrence of epithelial to mesenchymal transition (EMT) characteristics in EGFR-TKIs resistant NSCLC models, with and without acquisition of T790M mutation, and the ability of novel generation EGFR inhibitors to revert the resistant phenotype.

Methods

The following human NSCLC cell lines harboring EGFR activating mutations were used: HCC827 and PC9 NSCLC cell lines harboring EGFR activating mutation (del 746-750), the PC9-T790M (T790M+) and the HCC827-GR (T790M-) gefitinib resistant cells, and the H1975 carrying both EGFR activating and T790M mutations. The mesenchymal behavior and the effects of afatinib and osimertinib on resistant cell lines were studied both in vitro, by Western blot analysis, invasion, migration and anchorage-independent growth assays and in vivo, by metastatic assay in mice after tail vein injection with resistant cells.

Results

All gefitinib resistant cell lines, H1975, HCC827GR and PC9-T790M, exhibited significant higher protein expression of mesenchymal proteins, such as vimentin, Slug and VE-Cadherin and lost of E-Cadherin, as compared to gefitinib sensitive cells, with increased ability to migrate, invade and grow in anchorage-independent manner. Treatment with afatinib, and, to a greater extent, with osimertinib, strongly inhibited proliferation, migration, invasion and anchorage independent colon forming ability of H1975 and PC9-T790M cells, while effects were similar on HCC827-GR cells in vitro. Metastasic assay in vivo confirmed the superiority of osimertinib in T790M+ models

Conclusions

Collectively, these results suggest that EGFR mutant NSCLC cells resistant to first generation EGFR-TKI develop a mesenchymal phenotype, independently from the acquisition of T790M mutation. In this scenario, osimertinib is the most potent agent to overcome resistance and to revert the metastatic behavior of resistant cells.

Clinical trial identification

Legal entity responsible for the study

Second University of Naples

Funding

Second University of Naples

Disclosure

All authors have declared no conflicts of interest.

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