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.
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.
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.
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.
All authors have declared no conflicts of interest.