Clinical cancer research : an official journal of the American Association for Cancer Research · 2026
Inhibition of Acetyl-CoA-carboxylase induces endoplasmic reticulum stress and augments the efficacy of anti-cancer therapies.
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Shan Naing Lin, Balinda Henriette, Dai Jiawei, Wang Yueyue, Lin Hao-Kuen, Marczyk Michal, Espinoza Campos Gerson, Umlauf Sheila, McDermott Martina S J, Colorado Iriana, Lang Sabine M, Surovtseva Yulia V, Feinman Rena, Slamon Dennis J, Blenman Kim R M, Yan Qin, Muthusamy Viswanathan, Brenner Andrew J, Pusztai Lajos
Аннотация
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.
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.