Fatty Acid Synthase Inhibitor G28 Shows Anticancer Activity in EGFR Tyrosine Kinase Inhibitor Resistant Lung Adenocarcinoma Models

Abstract

Epidermal growth factor receptor (EGFR) tyrosine kinases inhibitors (TKIs) are effectivetherapies for non-small cell lung cancer (NSCLC) patients whose tumors harbor an EGFR activatingmutation. However, this treatment is not curative due to primary and secondary resistance suchas T790M mutation in exon 20. Recently, activation of transducer and activator of transcription 3(STAT3) in NSCLC appeared as an alternative resistance mechanism allowing cancer cells to elude theEGFR signaling. Overexpression of fatty acid synthase (FASN), a multifunctional enzyme essentialfor endogenous lipogenesis, has been related to resistance and the regulation of the EGFR/Jak2/STATsignaling pathways. Using EGFR mutated (EGFRm) NSCLC sensitive and EGFR TKIs' resistantmodels (Gefitinib Resistant, GR) we studied the role of the natural polyphenolic anti-FASN compound(−)-epigallocatechin-3-gallate (EGCG), and its derivative G28 to overcome EGFR TKIs' resistance.We show that G28's cytotoxicity is independent of TKIs' resistance mechanisms displaying synergisticeffects in combination with gefitinib and osimertinib in the resistant T790M negative (T790M−)model and showing a reduction of activated EGFR and STAT3 in T790M positive (T790M+) models.Our results provide the bases for further investigation of G28 in combination with TKIs to overcomethe EGFR TKI resistance in NSCLC.