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

Overview

Journal Cancers (Basel)

Publisher MDPI

Specialty Oncology

Date 2020 May 23

PMID 32438613

Citations 8

Authors

Emma Polonio-Alcala

Sonia Palomeras

Daniel Torres-Oteros

Joana Relat

Marta Planas

Lidia Feliu

Joaquim Ciurana

Santiago Ruiz-Martinez

Teresa Puig

Affiliations

Soon will be listed here.

Abstract

Epidermal growth factor receptor (EGFR) tyrosine kinases inhibitors (TKIs) are effective therapies for non-small cell lung cancer (NSCLC) patients whose tumors harbor an EGFR activating mutation. However, this treatment is not curative due to primary and secondary resistance such as 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 the EGFR signaling. Overexpression of fatty acid synthase (FASN), a multifunctional enzyme essential for endogenous lipogenesis, has been related to resistance and the regulation of the EGFR/Jak2/STAT signaling pathways. Using EGFR mutated (EGFRm) NSCLC sensitive and EGFR TKIs' resistant models (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 synergistic effects 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 overcome the EGFR TKI resistance in NSCLC.

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