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

e-Poster Display Session

3P - AZ12756122, a novel Fatty Acid Synthase (FASN) inhibitor, reduces resistance properties in Gefitinib- and Osimertinib resistant EGFR-mutated non-small cell lung cancer models

Date

24 Mar 2021

Session

e-Poster Display Session

Presenters

Emma Polonio-Alcalá

Citation

Journal of Thoracic Oncology (2021) 16 (suppl_4): S699-S703.

Authors

E. Polonio-Alcalá1, S. Palomeras2, R. Porta-Balanya3, J. Bosch-Barrera3, C.A. Vásquez4, J. Ciurana5, S. Ruiz-Martínez2, T. Puig2

Author affiliations

  • 1 Medical Sciences Department, University of Girona, Girona/ES
  • 2 University of Girona, 17004 - Girona/ES
  • 3 ICO Girona - Institut Català d'Oncologia Girona, 17007 - Girona/ES
  • 4 Institut Català de la Salut, 17007 - Girona/ES
  • 5 University of Girona, 17003 - Girona/ES
More

Abstract 3P

Background

Non-small cell lung cancer (NSCLC) is the most common subtype corresponding to roughly 85% of lung cancer patients. The discovery of activating mutations in the epidermal growth factor receptor (EGFRm) gene has led to an era of targeted therapy in lung cancer with EGFR tyrosine kinase inhibitors (TKIs). Although great progress has been accomplished, therapeutic improvement is necessary due to the constant appearance of resistance. Cancer stem cells (CSCs) are a small subpopulation responsible for tumour initiation and progression, recurrence, metastasis, and resistance to anti-cancer therapies. Furthermore, the overexpression and hyperactivation of fatty acid synthase (FASN) has been related to tumour aggressiveness and therapy resistance. Previously, we have shown that FASN inhibition causes cytotoxic effects in EGFRm lung adenocarcinoma cell models sensitive and resistant to EGFR-TKIs. Additionally, the combination of AZ12756122, a novel FASN inhibitor, with osimertinib exhibited a synergistic interaction. Therefore, we studied the effect of AZ12756122 in combination with osimertinib on EGFR, HER2, MAPK, STAT3 and AKT proteins in EGFRm NSCLC models sensitive and resistant to EGFR-TKIs. Moreover, the ability of AZ12756122 to target the CSC population was evaluated.

Methods

EGFRm lung adenocarcinoma models sensitive to EGFR-TKIs (PC9) and T790M- resistant to both gefitinib and osimertinib (PC9-GR3) were used. Gene and protein expression were assessed through qRT-PCR and Western blot, respectively. CSC population was evaluated by means of sphere-formation and clonogenic assays.

Results

The combination of AZ12756122 with osimertinib reduced FASN protein expression and the EGFR, HER2, AKT, MAPK, and STAT3 protein activation in the PC9-GR3 model. AZ12756122 treatment decreased the CSC properties tested of PC9 and PC9-GR3 models.

Conclusions

In conclusion, FASN inhibition caused by AZ12756122 arises as an encouraging therapeutic alternative to overcome resistance to EGFR-TKIs due to its synergistic interaction with osimertinib and its capacity to reduce CSC properties in EGFRm NSCLC cell models.

Legal entity responsible for the study

University of Girona.

Funding

AstraZeneca.

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