AZ12756122, a novel fatty acid synthase inhibitor, decreases resistance features in EGFR-TKI resistant EGFR-mutated NSCLC cell models

Different EGFR tyrosine kinase inhibitors (TKIs) have been developed for the treatment of non-small cell lung cancer (NSCLC) patients harboring sensitizing mutations in the EGFR gene. Apart from acquired secondary mutations, multiple resistance mechanisms have been reported, such as the overexpressi...

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Autores: Polonio Alcalá, Emma, Porta Balanyà, Rut, Ruiz Martínez, Santiago, Vásquez Dongo, Carmen Amalia, Relat, Joana, Bosch Barrera, Joaquim, Ciurana, Quim de, Puig i Miquel, Teresa
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2022
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:10256/21952
Acceso en línea:http://hdl.handle.net/10256/21952
Access Level:acceso abierto
Palabra clave:Inhibidors enzimàtics
Enzyme inhibitors
Càncer -- Tractament
Cancer -- Treatment
Pulmons -- Càncer -- Tractament
Lungs -- Cancer -- Treatment
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oai_identifier_str oai:recercat.cat:10256/21952
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spelling AZ12756122, a novel fatty acid synthase inhibitor, decreases resistance features in EGFR-TKI resistant EGFR-mutated NSCLC cell modelsPolonio Alcalá, EmmaPorta Balanyà, RutRuiz Martínez, SantiagoVásquez Dongo, Carmen AmaliaRelat, JoanaBosch Barrera, JoaquimCiurana, Quim dePuig i Miquel, TeresaInhibidors enzimàticsEnzyme inhibitorsCàncer -- TractamentCancer -- TreatmentPulmons -- Càncer -- TractamentLungs -- Cancer -- TreatmentDifferent EGFR tyrosine kinase inhibitors (TKIs) have been developed for the treatment of non-small cell lung cancer (NSCLC) patients harboring sensitizing mutations in the EGFR gene. Apart from acquired secondary mutations, multiple resistance mechanisms have been reported, such as the overexpression of fatty acid synthase (FASN), a multi-functional enzyme essential for the de novo lipogenesis, or the increase of cancer stem cells, a small subpopulation within the tumor responsible for relapse, metastasis, and resistance to therapies. Hence, the purpose of this work is to evaluate the novel FASN inhibitor AZ12756122, both alone and in combination with gefitinib and osimertinib, in EGFR-mutated (EGFRm) lung adenocarcinoma cell models sensitive and resistant to EGFR-TKIs. The molecular effect of AZ12756122 (alone and in combination with EGFR-TKI) on FASN, EGFR/ STAT3, Akt/mTOR, and MAPK signaling pathways was analyzed using RT-qPCR and Western blot. FASN expression was also evaluated in samples from patients with EGFRm NSCLC through immunohistochemistry. Our findings revealed that AZ12756122 caused cytotoxic effects inducing apoptosis, downregulated FASN expression and activity, decreased the activation of EGFR and Akt/mTOR pathway, and reduced cancer stem-like cells. Furthermore, the combination of AZ12756122 and osimertinib sensitized cells to EGFR-TKI, showing a syner- gistic effect that resulted in a reduction in the activation of EGFR, Akt/mTOR, and MAPK signaling pathways. Our study also showed that FASN+ EGFRm NSCLC patients exhibited a longer mPFS in patients who responded to EGFR-TKI treatment. In conclusion, FASN inhibition should be further studied for the treatment, alone or in combination with EGFR-TKIs, for EGFRm NSCLC patientsElsevier2022info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionpeer-reviewedapplication/pdfhttp://hdl.handle.net/10256/21952http://hdl.handle.net/10256/21952Biomedicine and Pharmacotherapy, 2022, vol. 156, art.núm. 113942Articles publicats (D-CM)Polonio Alcalá, Emma Porta Balanyà, Rut Ruiz Martínez, Santiago Vásquez Dongo, Carmen Amalia Relat, Joana Bosch Barrera, Joaquim Ciurana, Quim de Puig i Miquel, Teresa 2022 AZ12756122, a novel fatty acid synthase inhibitor, decreases resistance features in EGFR-TKI resistant EGFR-mutated NSCLC cell models Biomedicine & Pharmacotherapy 156 art.núm. 113942reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)Inglésinfo:eu-repo/semantics/altIdentifier/doi/10.1016/j.biopha.2022.113942info:eu-repo/semantics/altIdentifier/issn/0753-3322info:eu-repo/semantics/altIdentifier/eissn/1950-6007Reconeixement-NoComercial-SenseObraDerivada 4.0 Internacionalhttp://creativecommons.org/licenses/by-nc-nd/4.0info:eu-repo/semantics/openAccessoai:recercat.cat:10256/219522026-05-29T05:05:01Z
dc.title.none.fl_str_mv AZ12756122, a novel fatty acid synthase inhibitor, decreases resistance features in EGFR-TKI resistant EGFR-mutated NSCLC cell models
title AZ12756122, a novel fatty acid synthase inhibitor, decreases resistance features in EGFR-TKI resistant EGFR-mutated NSCLC cell models
spellingShingle AZ12756122, a novel fatty acid synthase inhibitor, decreases resistance features in EGFR-TKI resistant EGFR-mutated NSCLC cell models
Polonio Alcalá, Emma
Inhibidors enzimàtics
Enzyme inhibitors
Càncer -- Tractament
Cancer -- Treatment
Pulmons -- Càncer -- Tractament
Lungs -- Cancer -- Treatment
title_short AZ12756122, a novel fatty acid synthase inhibitor, decreases resistance features in EGFR-TKI resistant EGFR-mutated NSCLC cell models
title_full AZ12756122, a novel fatty acid synthase inhibitor, decreases resistance features in EGFR-TKI resistant EGFR-mutated NSCLC cell models
title_fullStr AZ12756122, a novel fatty acid synthase inhibitor, decreases resistance features in EGFR-TKI resistant EGFR-mutated NSCLC cell models
title_full_unstemmed AZ12756122, a novel fatty acid synthase inhibitor, decreases resistance features in EGFR-TKI resistant EGFR-mutated NSCLC cell models
title_sort AZ12756122, a novel fatty acid synthase inhibitor, decreases resistance features in EGFR-TKI resistant EGFR-mutated NSCLC cell models
dc.creator.none.fl_str_mv Polonio Alcalá, Emma
Porta Balanyà, Rut
Ruiz Martínez, Santiago
Vásquez Dongo, Carmen Amalia
Relat, Joana
Bosch Barrera, Joaquim
Ciurana, Quim de
Puig i Miquel, Teresa
author Polonio Alcalá, Emma
author_facet Polonio Alcalá, Emma
Porta Balanyà, Rut
Ruiz Martínez, Santiago
Vásquez Dongo, Carmen Amalia
Relat, Joana
Bosch Barrera, Joaquim
Ciurana, Quim de
Puig i Miquel, Teresa
author_role author
author2 Porta Balanyà, Rut
Ruiz Martínez, Santiago
Vásquez Dongo, Carmen Amalia
Relat, Joana
Bosch Barrera, Joaquim
Ciurana, Quim de
Puig i Miquel, Teresa
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Inhibidors enzimàtics
Enzyme inhibitors
Càncer -- Tractament
Cancer -- Treatment
Pulmons -- Càncer -- Tractament
Lungs -- Cancer -- Treatment
topic Inhibidors enzimàtics
Enzyme inhibitors
Càncer -- Tractament
Cancer -- Treatment
Pulmons -- Càncer -- Tractament
Lungs -- Cancer -- Treatment
description Different EGFR tyrosine kinase inhibitors (TKIs) have been developed for the treatment of non-small cell lung cancer (NSCLC) patients harboring sensitizing mutations in the EGFR gene. Apart from acquired secondary mutations, multiple resistance mechanisms have been reported, such as the overexpression of fatty acid synthase (FASN), a multi-functional enzyme essential for the de novo lipogenesis, or the increase of cancer stem cells, a small subpopulation within the tumor responsible for relapse, metastasis, and resistance to therapies. Hence, the purpose of this work is to evaluate the novel FASN inhibitor AZ12756122, both alone and in combination with gefitinib and osimertinib, in EGFR-mutated (EGFRm) lung adenocarcinoma cell models sensitive and resistant to EGFR-TKIs. The molecular effect of AZ12756122 (alone and in combination with EGFR-TKI) on FASN, EGFR/ STAT3, Akt/mTOR, and MAPK signaling pathways was analyzed using RT-qPCR and Western blot. FASN expression was also evaluated in samples from patients with EGFRm NSCLC through immunohistochemistry. Our findings revealed that AZ12756122 caused cytotoxic effects inducing apoptosis, downregulated FASN expression and activity, decreased the activation of EGFR and Akt/mTOR pathway, and reduced cancer stem-like cells. Furthermore, the combination of AZ12756122 and osimertinib sensitized cells to EGFR-TKI, showing a syner- gistic effect that resulted in a reduction in the activation of EGFR, Akt/mTOR, and MAPK signaling pathways. Our study also showed that FASN+ EGFRm NSCLC patients exhibited a longer mPFS in patients who responded to EGFR-TKI treatment. In conclusion, FASN inhibition should be further studied for the treatment, alone or in combination with EGFR-TKIs, for EGFRm NSCLC patients
publishDate 2022
dc.date.none.fl_str_mv 2022
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
peer-reviewed
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10256/21952
http://hdl.handle.net/10256/21952
url http://hdl.handle.net/10256/21952
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1016/j.biopha.2022.113942
info:eu-repo/semantics/altIdentifier/issn/0753-3322
info:eu-repo/semantics/altIdentifier/eissn/1950-6007
dc.rights.none.fl_str_mv Reconeixement-NoComercial-SenseObraDerivada 4.0 Internacional
http://creativecommons.org/licenses/by-nc-nd/4.0
info:eu-repo/semantics/openAccess
rights_invalid_str_mv Reconeixement-NoComercial-SenseObraDerivada 4.0 Internacional
http://creativecommons.org/licenses/by-nc-nd/4.0
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv Biomedicine and Pharmacotherapy, 2022, vol. 156, art.núm. 113942
Articles publicats (D-CM)
Polonio Alcalá, Emma Porta Balanyà, Rut Ruiz Martínez, Santiago Vásquez Dongo, Carmen Amalia Relat, Joana Bosch Barrera, Joaquim Ciurana, Quim de Puig i Miquel, Teresa 2022 AZ12756122, a novel fatty acid synthase inhibitor, decreases resistance features in EGFR-TKI resistant EGFR-mutated NSCLC cell models Biomedicine & Pharmacotherapy 156 art.núm. 113942
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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