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

Azhar Ali1, Elena Levantini2,3,4, Jun Ting Teo5

  • 1Cancer Science Institute of Singapore, National University of Singapore, Singapore City, Singapore csiazhar@nus.edu.sg csictm@nus.edu.sg daniel.tenen@nus.edu.sg.

EMBO Molecular Medicine
|February 17, 2018
PubMed

Insights

Targeting fatty acid metabolism with Orlistat can overcome acquired resistance to tyrosine kinase inhibitors in non-small cell lung cancer. This approach inhibits mutated epidermal growth factor receptor signaling, reducing tumor growth in EGFR-mutant NSCLC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Metabolism

Background:

  • Metabolic reprogramming is a key hallmark of cancer, enabling tumor cell survival.
  • Acquired resistance to tyrosine kinase inhibitors (TKIs) is a major challenge in treating non-small cell lung cancer (NSCLC).
  • Mutated epidermal growth factor receptor (EGFR) drives NSCLC, but resistance to EGFR-TKIs develops.

Purpose of the Study:

  • To identify novel therapeutic targets for acquired TKI resistance in EGFR-mutant NSCLC.
  • To investigate the role of fatty acid metabolism in mediating EGFR-TKI resistance.
  • To evaluate the efficacy of targeting fatty acid synthase (FASN) in resistant NSCLC models.

Main Methods:

  • Investigated a novel oncogenic signaling pathway in TKI-resistant EGFR-mutant NSCLC.
  • Examined the regulation of fatty acid synthase (FASN) by mutated EGFR.
  • Tested the effect of Orlistat, a FASN inhibitor, on EGFR signaling and tumor growth in vitro and in vivo.

Main Results:

  • Mutated EGFR signaling in TKI-resistant NSCLC depends on EGFR palmitoylation, regulated by FASN.
  • Inhibition of FASN by Orlistat leads to EGFR ubiquitination and abrogates mutant EGFR signaling.
  • Orlistat treatment reduced tumor growth in both cell culture systems and in vivo models.

Conclusions:

  • A functional link exists between mutated EGFR and FASN in acquired TKI resistance.
  • Targeting the fatty acid metabolism pathway, specifically FASN, is a promising strategy for overcoming TKI resistance in EGFR-mutant NSCLC patients.
  • Orlistat, an FDA-approved drug, demonstrates potential as a therapeutic agent for resistant NSCLC.
Keywords:
FASNNSCLCEGFR‐TKIacquired resistancepalmitoylation

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