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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology

4058 - Acquired resistance mechanism of Osimertinib targeting EGFR in human lung cancer

Date

21 Oct 2018

Session

Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology

Presenters

Vincenza Ciaramella

Citation

Annals of Oncology (2018) 29 (suppl_8): viii670-viii682. 10.1093/annonc/mdy304

Authors

V. Ciaramella, C.M. Della Corte, G. Barra, R. Di Liello, G. Viscardi, M. Orditura, E. Martinelli, F. Ciardiello, F. Morgillo

Author affiliations

  • Precision Medicine, Università degli studi della campania Luigi Vanvitelli, 80131 - Napoli/IT
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Resources

Abstract 4058

Background

Significant progress has been achieved by the development of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) targeting EGFR mutations in non-small cell lung cancer (NSCLC), however the acquisition of resistance to these agents are always the main cause of disease progression. Osimertinib (AZD9291), an oral potent drug, has developed as 3rd generation EGRF-TKIs with activities against sensitising mutations and the EGFR Thr790Met resistance mutation, which account for about 50% of the mechanisms of acquired resistance to 1st or 2nd generation EGFR-TKIs.

Methods

We developed in vitro model of acquired resistance to EGFR-inhibitors by treating human NSCLC cell lines with Osimertinib. PC9 and H1975 cell lines, which were initially sensitive to Osimertinib treatment (IC50: 0.1 and 0.5 µM, PC9 and H1975, respectively), became resistant after 8 months of continuous treatment reaching an IC50 ≈ 20 µM. This phenomenon was accompanied by visible morphological changes of the cells that acquire the typical characteristics of mesenchymal cells.

Results

We verified if this morphological change is translated into a functional change through the activation of specific pathways; protein lysates from harvested resistant cells showed higher levels of phosphorilation of EGFR, AKT and MAPK proteins than parental cell lines. We next examined whether resistant cell lines exhibit molecular changes known to occur during Epiteliali-to-Mesenchymal Transition (EMT) and we found a significant expression of mesenchymal protein like Vimentin, Snail and Slug in Osimertinib-resistant cells as compared to with Osimertinib-sensitive cells.

Conclusions

This data, indicates the importance of EMT as a crucial event in the acquisition of resistance to third-generation EGFR-TKIs inhibitors and suggests new opportunities to design new treatment strategies in lung cancer.

Clinical trial identification

Legal entity responsible for the study

Università degli Studi della Campania Luigi Vanvitelli.

Funding

Has not received any funding.

Editorial Acknowledgement

Disclosure

All authors have declared no conflicts of interest.

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