Senior Editor, OncLive®
Courtney Marabella joined the MJH Life Sciences team in 2021 and is Senior Editor for OncLive®. Prior to joining the company she worked as the Audience Development Editor for the Asbury Park Press, part of the USA Today Network. Email: firstname.lastname@example.org
The fatty acid synthase inhibition caused by AZ12756122 could represent a promising therapeutic alternative to overcome resistance to EGFR TKIs because of the synergistic interaction that it has with osimertinib and its ability to reduce cancer stem cell properties in EGFR-mutant non–small cell lung cancer cell models.
The fatty acid synthase (FASN) inhibition caused by AZ12756122 could represent a promising therapeutic alternative to overcome resistance to EGFR TKIs because of the synergistic interaction that it has with osimertinib (Tagrisso) and its ability to reduce cancer stem cell (CSC) properties in EGFR-mutant non–small cell lung cancer cell models, according to data from a study presented during the 2021 European Lung Cancer Virtual Congress.1
The combination of 25 mM of AZ12756122 and 1 mM of osimertinib demonstrated synergistic effects. No variations were observed in FASN messenger RNA (mRNA) and protein expression, and despite the increase in EGFR and STAT3 mRNA levels caused by the combination regimen, no change in their total protein expression was reported.
Additionally, mono- and co-treatments were found to decrease phosphorylated levels of EGRF and HER2, and a STAT3 activation was noted following osimertinib alone and combination treatments. AZ12756122 plus osimertinib also decreased phosphorylated levels of AKT, MAPK, and PRAS40.
Although a good deal of progress has been made in the development of EGFR TKIs, improvement is needed because of the emergence of resistance to these agents, that can be caused by CSCs. Additionally, it is known that FASN overexpression and hyperactivation has also been associated with tumor aggression and resistance to treatment.
The primary objective of this study was to examine the pharmacological interaction between AZ12756122 and osimertinib, and the impact the combination has on EGFR/STAT3 and HER2/AKT/MAPK signaling pathways in EGFR-mutant NSCLC models that are resistant to gefitinib (Iressa) and osimertinib. Additionally, investigators sought to evaluate how well AZ12756122 could target CSCs in EGFR-mutant NSCLC models that were both sensitive and resistant to gefitinib and osimertinib.
A cell proliferation assay was used to test the cytotoxic effect of AZ12756122/osimertinib for 72 hours. The effects of the combination were then examined through the assay and CompuSyn software was used to examine the pharmacological interaction between the 2 agents.
In terms of mRNA, changes in FASN, EGFR, and STAT3 levels were evaluated by reverse transcription quantitative real-time polymerase chain reaction. Additionally, changes in protein expression of FASN/EGFR/STAT3 and the HER2/AKT/MAPK signaling pathways were examined through the use of immunoblotting.
A sphere formation assay was used to grow cells in suspension for 7 days with AZ12756122 IC10 and IC30, and spheres that formed 50 mM or greater were then counted under an optic microscope. Additionally, cells were grown for 7 days with AZ12756122 IC10 and IC30. After, a crystal violet assay was done to fix and dye the colonies that developed.
Additional results indicated that treatment with AZ12756122 decreased the CSC properties tested in PC9 and PC9-GR3 models. Specifically, the FASN inhibitor was found to inhibit the ability of sphere formation and colony formation capacity.