Please use this identifier to cite or link to this item: https://doi.org/10.15252/emmm.201708313
Title: Fatty acid synthase mediates EGFR palmitoylation in EGFR mutated non-small cell lung cancer
Authors: Ali, A 
Levantini, E
Teo, J.T 
Goggi, J 
Clohessy, J.G
Wu, C.S 
Chen, L 
Yang, H 
Krishnan, I
Kocher, O
Zhang, J
Soo, R.A 
Bhakoo, K 
Chin, T.M 
Tenen, D.G 
Keywords: epidermal growth factor receptor
fatty acid synthase
gefitinib
protein tyrosine kinase inhibitor
tetrahydrolipstatin
EGFR protein, human
epidermal growth factor receptor
fatty acid
fatty acid synthase
protein kinase B
protein kinase inhibitor
tetrahydrolipstatin
animal cell
animal experiment
animal model
antineoplastic activity
Article
cancer inhibition
cell cycle
cell proliferation
cell viability
controlled study
enzyme inhibition
fatty acid metabolism
female
human
human cell
in vivo study
male
mouse
non small cell lung cancer
nonhuman
palmitoylation
priority journal
signal transduction
transgenic mouse
tumor resistance
tumor volume
tumor xenograft
ubiquitination
animal
antagonists and inhibitors
biological model
drug effect
drug resistance
drug screening
gene expression regulation
gene silencing
genetics
lipoylation
lung tumor
metabolism
mutation
non small cell lung cancer
pathology
tumor cell line
upregulation
Animals
Carcinoma, Non-Small-Cell Lung
Cell Line, Tumor
Cell Proliferation
Drug Resistance, Neoplasm
ErbB Receptors
Fatty Acid Synthases
Fatty Acids
Gene Expression Regulation, Neoplastic
Gene Silencing
Lipoylation
Lung Neoplasms
Male
Mice, Transgenic
Models, Biological
Mutation
Orlistat
Protein Kinase Inhibitors
Proto-Oncogene Proteins c-akt
Signal Transduction
Ubiquitination
Up-Regulation
Xenograft Model Antitumor Assays
Issue Date: 2018
Citation: Ali, A, Levantini, E, Teo, J.T, Goggi, J, Clohessy, J.G, Wu, C.S, Chen, L, Yang, H, Krishnan, I, Kocher, O, Zhang, J, Soo, R.A, Bhakoo, K, Chin, T.M, Tenen, D.G (2018). Fatty acid synthase mediates EGFR palmitoylation in EGFR mutated non-small cell lung cancer. EMBO Molecular Medicine 10 (3) : e8313. ScholarBank@NUS Repository. https://doi.org/10.15252/emmm.201708313
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. © 2018 The Authors. Published under the terms of the CC BY 4.0 license
Source Title: EMBO Molecular Medicine
URI: https://scholarbank.nus.edu.sg/handle/10635/173737
ISSN: 17574676
DOI: 10.15252/emmm.201708313
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