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

Purpose: 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. Experimental Design: 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. Results: 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. Conclusions: 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.