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Fatty acid synthase mediates EGFR palmitoylation in EGFR mutated non-small cell lung cancer. (EMBO Mol Med, Feb 2018)

Ali A1, Levantini E2,3,4, Teo JT5, Goggi J6, Clohessy JG3, Wu CS5, Chen L5, Yang H5, Krishnan I3, Kocher O3, Zhang J3, Soo RA5,7, Bhakoo K6, Chin TM1,8, Tenen DG1,2.

Author information:
1 Cancer Science Institute of Singapore, National University of Singapore, Singapore City, Singapore
2 Harvard Stem Cell Institute, Harvard Medical School, Boston, MA, USA.
3 Beth Israel Deaconess Medical Center, Boston, MA, USA.
4 Institute of Biomedical Technologies, National Research Council (CNR), Pisa, Italy.
5 Cancer Science Institute of Singapore, National University of Singapore, Singapore City, Singapore.
6 Singapore Bioimaging Consortium (A*STAR), Singapore City, Singapore.
7 Department of Hematology-Oncology, National University Cancer Institute, National University Health System, Singapore City, Singapore.
8 Raffles Cancer Centre, Raffles Hospital, Singapore City, Singapore.

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.

KEYWORDS: FASN ; NSCLC ; EGFR‐TKI; acquired resistance; palmitoylation

PMID: 29449326