Inhibition of Acetyl-CoA-carboxylase induces endoplasmic reticulum stress and augments the efficacy of anti-cancer therapies.

Abstract

Increased dependence on de novo fatty acid synthesis is a key feature of metabolic rewiring in cancer cells. Acetyl-CoA-carboxylase (ACC) is the rate limiting enzyme of de novo fatty acid synthesis. We examined the anti-cancer activity of the ACC inhibitor, PF-05175157, alone and in combination with approved anticancer therapies. PF-05175157 activity was assessed in high throughput cell line screen and in mouse xenograft experiments. Drug-drug interactions were tested with 166 FDA-approved agents. Mechanistic studies included lipid profiling and evaluation of endoplasmic reticulum (ER) stress and unfolded protein response markers and downstream effects on cellular metabolism and viability. PF-05175157 showed broad anti-cancer activity including in cells resistant to targeted therapies and inhibited tumor growth in xenograft experiments. Combination studies demonstrated enhanced efficacy with multiple FDA-approved anti-cancer drugs, including tyrosine kinase inhibitors and chemotherapy agents. Lipid profiling showed increase in cholesterol esters and unsaturated long-chain fatty acids that alter membrane fluidity. These changes were associated with evidence of ER stress and unfolded protein response followed by metabolic arrest leading to cell death. ACC inhibition with PF-05175157 has a potential for clinical application as an anti-cancer agent and due to its unique mechanism of action and broad synergy with existing anti-cancer therapies.