Journal Article

Fatty acid synthase mediates EGFR palmitoylation in EGFR mutated non‐small cell lung cancer

Levantini, Elena, Soo, Ross A, Zhang, Junyan, Teo, Jun Ting, Clohessy, John G, Yang, Henry, Krishnan, Indira, Bhakoo, Kishore, Tenen, Daniel G, Goggi, Julian, Ali, Azhar, Kocher, Olivier, Chen, Leilei, Wu, Chan Shuo, Chin, Tan Min

2018

Overview

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. Synopsis In EGFR mutated Non‐Small Cell Lung Carcinoma with acquired Tyrosine Kinase Inhibitors resistance, FASN mediates EGFR palmitoylation and supports tumor growth. With limited effective therapeutics, these data show that FASN is a candidate target for acquired TKI‐resistant EGFR mutant NSCLC. Identification of a positive feedback loop involving mutated EGFR and FASN in EGFR mutated NSCLC with acquired TKI resistance. FASN‐mediated EGFR palmitoylaton is crucial for survival of NSCLC cells, and influences its translocation to the nucleus. FASN inhibition suppresses tumor growth in both cell culture systems and in vivo models, highlighting its potential as a target for therapeutic intervention. Graphical Abstract In EGFR mutated Non‐Small Cell Lung Carcinoma with acquired Tyrosine Kinase Inhibitors resistance, FASN mediates EGFR palmitoylation and supports tumor growth. With limited effective therapeutics, these data show that FASN is a candidate target for acquired TKI‐resistant EGFR mutant NSCLC.

• Publisher: Nature Publishing Group UK,EMBO Press,John Wiley and Sons Inc,Springer Nature
• Subject: acquired resistance / Animals / Carcinoma, Non-Small-Cell Lung - genetics / Carcinoma, Non-Small-Cell Lung - pathology / Cell culture / Cell Line, Tumor / Cell Proliferation - drug effects / Drug Resistance, Neoplasm - drug effects / Drug Resistance, Neoplasm - genetics / EGFR‐TKI / EMBO03 / EMBO12 / EMBO28 / Enzyme inhibitors / Epidermal growth factor / Epidermal growth factor receptors / ErbB Receptors - genetics / FASN / Fatty Acid Synthases - antagonists & inhibitors / Fatty Acid Synthases - metabolism / Fatty acids / Fatty Acids - metabolism / Fatty-acid synthase / Gene Expression Regulation, Neoplastic - drug effects / Gene Silencing - drug effects / Kinases / Lipoylation / Lung cancer / Lung carcinoma / Lung Neoplasms - genetics / Lung Neoplasms - pathology / Male / Mice, Transgenic / Models, Biological / Mutation - genetics / Non-small cell lung carcinoma / NSCLC / Orlistat - pharmacology / Palmitic acid / Palmitoylation / Protein Kinase Inhibitors - pharmacology / Protein-tyrosine kinase / Proto-Oncogene Proteins c-akt - metabolism / Research Article / Signal transduction / Signal Transduction - drug effects / Small cell lung carcinoma / Tumor cells / Ubiquitination / Ubiquitination - drug effects / Up-Regulation - drug effects / Up-Regulation - genetics / Xenograft Model Antitumor Assays