Fatty acid synthase (FASN) inhibition cooperates with BH3 mimetic drugs to overcome resistance to mitochondrial apoptosis in pancreatic cancer
Resistance to mitochondrial apoptosis is a major driver of chemoresistance in pancreatic ductal adenocarcinoma (PDAC). However, pharmacological manipulation of the mitochondrial apoptosis threshold in PDAC cells remains an unmet therapeutic goal. We hypothesized that fatty acid synthase inhibitors (...
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Elsevier
2025-04-01
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| Series: | Neoplasia: An International Journal for Oncology Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558625000223 |
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| author | Travis Vander Steen Ingrid Espinoza Cristina Duran Guillem Casadevall Eila Serrano-Hervás Elisabet Cuyàs Sara Verdura George Kemble Scott H. Kaufmann Robert McWilliams Sílvia Osuna Daniel D. Billadeau Javier A. Menendez Ruth Lupu |
| author_facet | Travis Vander Steen Ingrid Espinoza Cristina Duran Guillem Casadevall Eila Serrano-Hervás Elisabet Cuyàs Sara Verdura George Kemble Scott H. Kaufmann Robert McWilliams Sílvia Osuna Daniel D. Billadeau Javier A. Menendez Ruth Lupu |
| author_sort | Travis Vander Steen |
| collection | DOAJ |
| description | Resistance to mitochondrial apoptosis is a major driver of chemoresistance in pancreatic ductal adenocarcinoma (PDAC). However, pharmacological manipulation of the mitochondrial apoptosis threshold in PDAC cells remains an unmet therapeutic goal. We hypothesized that fatty acid synthase inhibitors (FASNis), a family of targeted metabolic therapeutics recently entering the clinic, could lower the apoptotic threshold in chemoresistant PDAC cells and be synergistic with BH3 mimetics that neutralize anti-apoptotic proteins. Computational studies with TVB-3166 and TVB-3664, two analogues of the clinical-grade FASNi TVB-2640 (denifanstat), confirmed their uncompetitive behavior towards NADPH when bound to the FASN ketoacyl reductase domain. The extent of NADPH accumulation, a consequence of FASN inhibition, paralleled the sensitivity of PDAC cells to the apoptotic effects of TVB FASNis in conventional PDAC cell lines that naturally express varying levels of FASN. FASN inhibition dramatically increased the sensitivity of “FASN-high” expressing PDAC cells to the BCL2/BCL-XL/BCL-W inhibitor ABT-263/navitoclax and the BCL2-selective inhibitor ABT-199/venetoclax, both in vitro and in in vivo xenografted tumors. The ability of TVB FASNis to shift the balance of pro- and anti-apoptotic proteins and thereby push PDAC cells closer to the apoptotic threshold was also observed in cell lines developed from patient-derived xenografts (PDXs) representative of the classical (pancreatic) transcriptomic subtype of PDAC. Experiments in PDAC PDXs in vivo confirmed the synergistic antitumor activity of TVB-3664 with navitoclax and venetoclax, independent of the nature of the replication stress signature of patient-derived PDAC cells. The discovery that targeted inhibition of FASN is a metabolic perturbation that sensitizes PDAC cells to BH3 mimetics warrants further investigation to overcome resistance to mitochondrial apoptosis in PDAC patients. |
| format | Article |
| id | doaj-art-ba6bc971ac2a4b7b8c3617e49f7f66c9 |
| institution | DOAJ |
| issn | 1476-5586 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj-art-ba6bc971ac2a4b7b8c3617e49f7f66c92025-08-20T02:55:46ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55862025-04-016210114310.1016/j.neo.2025.101143Fatty acid synthase (FASN) inhibition cooperates with BH3 mimetic drugs to overcome resistance to mitochondrial apoptosis in pancreatic cancerTravis Vander Steen0Ingrid Espinoza1Cristina Duran2Guillem Casadevall3Eila Serrano-Hervás4Elisabet Cuyàs5Sara Verdura6George Kemble7Scott H. Kaufmann8Robert McWilliams9Sílvia Osuna10Daniel D. Billadeau11Javier A. Menendez12Ruth Lupu13Division of Experimental Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USANational Institute of Health, National Heart Lung and Blood Institute (NHLBI), Bethesda, MD 20817, USA; Lung Development and Pediatric Branch (HNH36), Bethesda, MD 20817, USAInstitut de Química Computacional i Catàlisi and Departament de Química, Universitat de Girona, Girona 17003, SpainInstitut de Química Computacional i Catàlisi and Departament de Química, Universitat de Girona, Girona 17003, SpainProgram Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology, Girona 17007, Spain; Metabolism and Cancer Group,Girona Biomedical Research Institute (IDIBGI), Salt 17190, Girona, SpainProgram Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology, Girona 17007, Spain; Metabolism and Cancer Group,Girona Biomedical Research Institute (IDIBGI), Salt 17190, Girona, SpainProgram Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology, Girona 17007, Spain; Metabolism and Cancer Group,Girona Biomedical Research Institute (IDIBGI), Salt 17190, Girona, SpainSagimet Biosciences Inc., San Mateo, CA 94402, USAMayo Clinic Cancer Center, Rochester, MN 55905, USA; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, 55905, USA; Division of Oncology Research, Mayo Clinic, Rochester, MN, 55905, USAMayo Clinic Cancer Center, Rochester, MN 55905, USA; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, 55905, USAInstitut de Química Computacional i Catàlisi and Departament de Química, Universitat de Girona, Girona 17003, Spain; ICREA, Barcelona 08010, SpainMayo Clinic Cancer Center, Rochester, MN 55905, USA; Division of Oncology Research, Mayo Clinic, Rochester, MN, 55905, USA; Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA; Department of Immunology College of Medicine, Mayo Clinic, Rochester, MN 55905, USAProgram Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology, Girona 17007, Spain; Metabolism and Cancer Group,Girona Biomedical Research Institute (IDIBGI), Salt 17190, Girona, Spain; Corresponding author at: Edifici M2, Parc Hospitalari Martí i Julià, E-17190, Salt (Girona), Spain, Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology (ICO), Girona Biomedical Research Institute.Division of Experimental Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA; Mayo Clinic Cancer Center, Rochester, MN 55905, USA; Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA; Corresponding author at: 200 First Street SW, Rochester, Minnesota 55905, USA, Biochemistry and Molecular Biology, Experimental Pathology and Medicine, Mayo Clinic College of Medicine, Mayo Clinic Cancer Center.Resistance to mitochondrial apoptosis is a major driver of chemoresistance in pancreatic ductal adenocarcinoma (PDAC). However, pharmacological manipulation of the mitochondrial apoptosis threshold in PDAC cells remains an unmet therapeutic goal. We hypothesized that fatty acid synthase inhibitors (FASNis), a family of targeted metabolic therapeutics recently entering the clinic, could lower the apoptotic threshold in chemoresistant PDAC cells and be synergistic with BH3 mimetics that neutralize anti-apoptotic proteins. Computational studies with TVB-3166 and TVB-3664, two analogues of the clinical-grade FASNi TVB-2640 (denifanstat), confirmed their uncompetitive behavior towards NADPH when bound to the FASN ketoacyl reductase domain. The extent of NADPH accumulation, a consequence of FASN inhibition, paralleled the sensitivity of PDAC cells to the apoptotic effects of TVB FASNis in conventional PDAC cell lines that naturally express varying levels of FASN. FASN inhibition dramatically increased the sensitivity of “FASN-high” expressing PDAC cells to the BCL2/BCL-XL/BCL-W inhibitor ABT-263/navitoclax and the BCL2-selective inhibitor ABT-199/venetoclax, both in vitro and in in vivo xenografted tumors. The ability of TVB FASNis to shift the balance of pro- and anti-apoptotic proteins and thereby push PDAC cells closer to the apoptotic threshold was also observed in cell lines developed from patient-derived xenografts (PDXs) representative of the classical (pancreatic) transcriptomic subtype of PDAC. Experiments in PDAC PDXs in vivo confirmed the synergistic antitumor activity of TVB-3664 with navitoclax and venetoclax, independent of the nature of the replication stress signature of patient-derived PDAC cells. The discovery that targeted inhibition of FASN is a metabolic perturbation that sensitizes PDAC cells to BH3 mimetics warrants further investigation to overcome resistance to mitochondrial apoptosis in PDAC patients.http://www.sciencedirect.com/science/article/pii/S1476558625000223Pancreatic cancerFatty acid synthaseBH3 mimeticsGemcitabine |
| spellingShingle | Travis Vander Steen Ingrid Espinoza Cristina Duran Guillem Casadevall Eila Serrano-Hervás Elisabet Cuyàs Sara Verdura George Kemble Scott H. Kaufmann Robert McWilliams Sílvia Osuna Daniel D. Billadeau Javier A. Menendez Ruth Lupu Fatty acid synthase (FASN) inhibition cooperates with BH3 mimetic drugs to overcome resistance to mitochondrial apoptosis in pancreatic cancer Neoplasia: An International Journal for Oncology Research Pancreatic cancer Fatty acid synthase BH3 mimetics Gemcitabine |
| title | Fatty acid synthase (FASN) inhibition cooperates with BH3 mimetic drugs to overcome resistance to mitochondrial apoptosis in pancreatic cancer |
| title_full | Fatty acid synthase (FASN) inhibition cooperates with BH3 mimetic drugs to overcome resistance to mitochondrial apoptosis in pancreatic cancer |
| title_fullStr | Fatty acid synthase (FASN) inhibition cooperates with BH3 mimetic drugs to overcome resistance to mitochondrial apoptosis in pancreatic cancer |
| title_full_unstemmed | Fatty acid synthase (FASN) inhibition cooperates with BH3 mimetic drugs to overcome resistance to mitochondrial apoptosis in pancreatic cancer |
| title_short | Fatty acid synthase (FASN) inhibition cooperates with BH3 mimetic drugs to overcome resistance to mitochondrial apoptosis in pancreatic cancer |
| title_sort | fatty acid synthase fasn inhibition cooperates with bh3 mimetic drugs to overcome resistance to mitochondrial apoptosis in pancreatic cancer |
| topic | Pancreatic cancer Fatty acid synthase BH3 mimetics Gemcitabine |
| url | http://www.sciencedirect.com/science/article/pii/S1476558625000223 |
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