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

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.

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.

Source: EMBO Molecular Medicine - February 1, 2018 Category: Molecular Biology Authors: 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 Tags: Research Article Source Type: research