Fatty acid synthase mediates EGFR palmitoylation in EGFR mutated non‐small cell lung cancer
Abstract Metabolic reprogramming is widely known as a hallmark of cancer cells to allow adaptation of cells to sustain survival signals. In this report, we describe a novel oncogenic signaling pathway exclusively acting in mutated epidermal growth factor receptor (EGFR) non‐small cell lung cancer (N...
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| Format: | Article |
| Language: | English |
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Springer Nature
2018-02-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201708313 |
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| _version_ | 1849343557615222784 |
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| author | Azhar Ali Elena Levantini Jun Ting Teo Julian Goggi John G Clohessy Chan Shuo Wu Leilei Chen Henry Yang Indira Krishnan Olivier Kocher Junyan Zhang Ross A Soo Kishore Bhakoo Tan Min Chin Daniel G Tenen |
| author_facet | Azhar Ali Elena Levantini Jun Ting Teo Julian Goggi John G Clohessy Chan Shuo Wu Leilei Chen Henry Yang Indira Krishnan Olivier Kocher Junyan Zhang Ross A Soo Kishore Bhakoo Tan Min Chin Daniel G Tenen |
| author_sort | Azhar Ali |
| collection | DOAJ |
| description | Abstract Metabolic reprogramming is widely known as a hallmark of cancer cells to allow adaptation of cells to sustain survival signals. In this report, we describe a novel oncogenic signaling pathway exclusively acting in mutated epidermal growth factor receptor (EGFR) non‐small cell lung cancer (NSCLC) with acquired tyrosine kinase inhibitor (TKI) resistance. Mutated EGFR mediates TKI resistance through regulation of the fatty acid synthase (FASN), which produces 16‐C saturated fatty acid palmitate. Our work shows that the persistent signaling by mutated EGFR in TKI‐resistant tumor cells relies on EGFR palmitoylation and can be targeted by Orlistat, an FDA‐approved anti‐obesity drug. Inhibition of FASN with Orlistat induces EGFR ubiquitination and abrogates EGFR mutant signaling, and reduces tumor growths both in culture systems and in vivo. Together, our data provide compelling evidence on the functional interrelationship between mutated EGFR and FASN and that the fatty acid metabolism pathway is a candidate target for acquired TKI‐resistant EGFR mutant NSCLC patients. |
| format | Article |
| id | doaj-art-01c6764a906741acac6682d904e68f0a |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2018-02-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-01c6764a906741acac6682d904e68f0a2025-08-20T03:42:56ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842018-02-0110311910.15252/emmm.201708313Fatty acid synthase mediates EGFR palmitoylation in EGFR mutated non‐small cell lung cancerAzhar Ali0Elena Levantini1Jun Ting Teo2Julian Goggi3John G Clohessy4Chan Shuo Wu5Leilei Chen6Henry Yang7Indira Krishnan8Olivier Kocher9Junyan Zhang10Ross A Soo11Kishore Bhakoo12Tan Min Chin13Daniel G Tenen14Cancer Science Institute of Singapore, National University of SingaporeHarvard Stem Cell Institute, Harvard Medical SchoolCancer Science Institute of Singapore, National University of SingaporeSingapore Bioimaging Consortium (A*STAR)Beth Israel Deaconess Medical CenterCancer Science Institute of Singapore, National University of SingaporeCancer Science Institute of Singapore, National University of SingaporeCancer Science Institute of Singapore, National University of SingaporeBeth Israel Deaconess Medical CenterBeth Israel Deaconess Medical CenterBeth Israel Deaconess Medical CenterCancer Science Institute of Singapore, National University of SingaporeSingapore Bioimaging Consortium (A*STAR)Cancer Science Institute of Singapore, National University of SingaporeCancer Science Institute of Singapore, National University of SingaporeAbstract Metabolic reprogramming is widely known as a hallmark of cancer cells to allow adaptation of cells to sustain survival signals. In this report, we describe a novel oncogenic signaling pathway exclusively acting in mutated epidermal growth factor receptor (EGFR) non‐small cell lung cancer (NSCLC) with acquired tyrosine kinase inhibitor (TKI) resistance. Mutated EGFR mediates TKI resistance through regulation of the fatty acid synthase (FASN), which produces 16‐C saturated fatty acid palmitate. Our work shows that the persistent signaling by mutated EGFR in TKI‐resistant tumor cells relies on EGFR palmitoylation and can be targeted by Orlistat, an FDA‐approved anti‐obesity drug. Inhibition of FASN with Orlistat induces EGFR ubiquitination and abrogates EGFR mutant signaling, and reduces tumor growths both in culture systems and in vivo. Together, our data provide compelling evidence on the functional interrelationship between mutated EGFR and FASN and that the fatty acid metabolism pathway is a candidate target for acquired TKI‐resistant EGFR mutant NSCLC patients.https://doi.org/10.15252/emmm.201708313acquired resistanceEGFR‐TKIFASNNSCLCpalmitoylation |
| spellingShingle | Azhar Ali Elena Levantini Jun Ting Teo Julian Goggi John G Clohessy Chan Shuo Wu Leilei Chen Henry Yang Indira Krishnan Olivier Kocher Junyan Zhang Ross A Soo Kishore Bhakoo Tan Min Chin Daniel G Tenen Fatty acid synthase mediates EGFR palmitoylation in EGFR mutated non‐small cell lung cancer EMBO Molecular Medicine acquired resistance EGFR‐TKI FASN NSCLC palmitoylation |
| title | Fatty acid synthase mediates EGFR palmitoylation in EGFR mutated non‐small cell lung cancer |
| title_full | Fatty acid synthase mediates EGFR palmitoylation in EGFR mutated non‐small cell lung cancer |
| title_fullStr | Fatty acid synthase mediates EGFR palmitoylation in EGFR mutated non‐small cell lung cancer |
| title_full_unstemmed | Fatty acid synthase mediates EGFR palmitoylation in EGFR mutated non‐small cell lung cancer |
| title_short | Fatty acid synthase mediates EGFR palmitoylation in EGFR mutated non‐small cell lung cancer |
| title_sort | fatty acid synthase mediates egfr palmitoylation in egfr mutated non small cell lung cancer |
| topic | acquired resistance EGFR‐TKI FASN NSCLC palmitoylation |
| url | https://doi.org/10.15252/emmm.201708313 |
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