TY  - GEN
TI  - Fatty Acid Synthase Inhibitor G28 Shows Anticancer Activity in EGFR Tyrosine Kinase Inhibitor Resistant Lung Adenocarcinoma Models
AU  - Polonio Alcalá, Emma
AU  - Palomeras Pairet, Sònia
AU  - Torres Oteros, Daniel
AU  - Relat, Joana
AU  - Planas i Grabuleda, Marta
AU  - Feliu Soley, Lídia
AU  - Ciurana, Quim de
AU  - Ruiz Martínez, Santiago
AU  - Puig i Miquel, Teresa
PY  - 2020
PB  - MDPI (Multidisciplinary Digital Publishing Institute)
LA  - eng
KW  - Inhibidors enzimàtics
KW  - Enzyme inhibitors
KW  - Càncer -- Tractament
KW  - Cancer -- Treatment
KW  - Pulmons -- Càncer -- Tractament
KW  - Lungs -- Cancer -- Treatment
AB  - 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. ; The authors acknowledge the financial support from AstraZeneca, the E. P.-A pre-doctoral grant (2019FI_B01011), and the support of the Catalan Government (2017SGR00385)
UR  - http://hdl.handle.net/10256/18121
UR  - https://www.pollux-fid.de/r/base-ftunivgironadugi:oai:dugi-doc.udg.edu:10256/18121
H1  - Pollux (Fachinformationsdienst Politikwissenschaft)
ER  -