Fatty Acid Synthase Inhibitor G28 Shows Anticancer Activity in EGFR Tyrosine Kinase Inhibitor Resistant Lung Adenocarcinoma Models
dc.contributor.author
dc.date.accessioned
2020-06-09T07:04:52Z
dc.date.available
2020-06-09T07:04:52Z
dc.date.issued
2020-05-19
dc.identifier.uri
dc.description.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.
dc.description.sponsorship
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)
dc.format.mimetype
application/pdf
dc.language.iso
eng
dc.publisher
MDPI (Multidisciplinary Digital Publishing Institute)
dc.relation.isformatof
Reproducció digital del document publicat a: https://doi.org/10.3390/cancers12051283
dc.relation.ispartof
Cancers, 2020, vol. 12, núm. 5, p. 1283
dc.relation.ispartofseries
Articles publicats (D-CM)
dc.rights
Attribution 4.0 International
dc.rights.uri
dc.subject
dc.title
Fatty Acid Synthase Inhibitor G28 Shows Anticancer Activity in EGFR Tyrosine Kinase Inhibitor Resistant Lung Adenocarcinoma Models
dc.type
info:eu-repo/semantics/article
dc.rights.accessRights
info:eu-repo/semantics/openAccess
dc.type.version
info:eu-repo/semantics/publishedVersion
dc.identifier.doi
dc.identifier.idgrec
031517
dc.type.peerreviewed
peer-reviewed
dc.identifier.eissn
2072-6694