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...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-12-01
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| Series: | Biomedicine & Pharmacotherapy |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0753332222013312 |
| _version_ | 1811221047448436736 |
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| author | Emma Polonio-Alcalá Rut Porta Santiago Ruiz-Martínez Carmen Vásquez-Dongo Joana Relat Joaquim Bosch-Barrera Joaquim Ciurana Teresa Puig |
| author_facet | Emma Polonio-Alcalá Rut Porta Santiago Ruiz-Martínez Carmen Vásquez-Dongo Joana Relat Joaquim Bosch-Barrera Joaquim Ciurana Teresa Puig |
| author_sort | Emma Polonio-Alcalá |
| collection | DOAJ |
| 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 synergistic 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. |
| first_indexed | 2024-04-12T07:52:58Z |
| format | Article |
| id | doaj.art-1840517f642547c1832e17519daa97d8 |
| institution | Directory Open Access Journal |
| issn | 0753-3322 |
| language | English |
| last_indexed | 2024-04-12T07:52:58Z |
| publishDate | 2022-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Biomedicine & Pharmacotherapy |
| spelling | doaj.art-1840517f642547c1832e17519daa97d82022-12-22T03:41:33ZengElsevierBiomedicine & Pharmacotherapy0753-33222022-12-01156113942AZ12756122, a novel fatty acid synthase inhibitor, decreases resistance features in EGFR-TKI resistant EGFR-mutated NSCLC cell modelsEmma Polonio-Alcalá0Rut Porta1Santiago Ruiz-Martínez2Carmen Vásquez-Dongo3Joana Relat4Joaquim Bosch-Barrera5Joaquim Ciurana6Teresa Puig7New Therapeutic Targets Laboratory (TargetsLab)-Oncology Unit, Department of Medical Sciences, University of Girona, Spain; Product, Process and Production Engineering Research Group (GREP), Department of Mechanical Engineering and Industrial Construction, University of Girona, SpainNew Therapeutic Targets Laboratory (TargetsLab)-Oncology Unit, Department of Medical Sciences, University of Girona, Spain; Medical Oncology Department, Catalan Institute of Oncology, SpainNew Therapeutic Targets Laboratory (TargetsLab)-Oncology Unit, Department of Medical Sciences, University of Girona, SpainNew Therapeutic Targets Laboratory (TargetsLab)-Oncology Unit, Department of Medical Sciences, University of Girona, Spain; Department of Pathology, Dr. Josep Trueta University Hospital, SpainDepartment of Nutrition, Food Sciences and Gastronomy, School of Pharmacy and Food Sciences, Food Torribera Campus, University of Barcelona, Spain; Institute of Nutrition and Food Safety of the University of Barcelona (INSA-UB), Spain; CIBER Physiopathology of Obesity and Nutrition (CIBER-OBN), Instituto de Salud Carlos III, SpainMedical Oncology Department, Catalan Institute of Oncology, SpainProduct, Process and Production Engineering Research Group (GREP), Department of Mechanical Engineering and Industrial Construction, University of Girona, Spain; Correspondence to: Product, Process and Production Engineering Research Group (GREP), Department of Mechanical Engineering and Industrial Construction, University of Girona, 17003 Girona, Spain.New Therapeutic Targets Laboratory (TargetsLab)-Oncology Unit, Department of Medical Sciences, University of Girona, Spain; Correspondence to: New Therapeutic Targets Laboratory (TargetsLab)-Oncology Unit, Department of Medical Sciences, University of Girona, Girona 17003, Spain.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 synergistic 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.http://www.sciencedirect.com/science/article/pii/S0753332222013312NSCLCFASNEGFROsimertinibDrug combination |
| spellingShingle | Emma Polonio-Alcalá Rut Porta Santiago Ruiz-Martínez Carmen Vásquez-Dongo Joana Relat Joaquim Bosch-Barrera Joaquim Ciurana Teresa Puig AZ12756122, a novel fatty acid synthase inhibitor, decreases resistance features in EGFR-TKI resistant EGFR-mutated NSCLC cell models Biomedicine & Pharmacotherapy NSCLC FASN EGFR Osimertinib Drug combination |
| title | 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_short | 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 |
| topic | NSCLC FASN EGFR Osimertinib Drug combination |
| url | http://www.sciencedirect.com/science/article/pii/S0753332222013312 |
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