2. Academic Validation
  3. Targeting Acetyl-CoA Carboxylase Suppresses De Novo Lipogenesis and Tumor Cell Growth in Multiple Myeloma

Targeting Acetyl-CoA Carboxylase Suppresses De Novo Lipogenesis and Tumor Cell Growth in Multiple Myeloma

  • Clin Cancer Res. 2025 Mar 7. doi: 10.1158/1078-0432.CCR-24-2000.
Eugenio Morelli 1,  Caroline Fidalgo Ribeiro 2,  Silvia D Rodrigues 3,  Claire Gao 4,  Fabio Socciarelli 5,  Domenico Maisano 4,  Vanessa Favasuli 4,  Na Liu 4,  Katia Todoerti 6,  Chandraditya Chakraborty 7,  Yao Yao 8,  Mariateresa Fulciniti 9,  Mehmet Samur 10,  Anil Aktas-Samur 7,  Nicola Amodio 11,  Marcello Turi 12,  Francesca Barello 12,  Johany Penailillo 13,  Cesarina Giallongo 14,  Alessandra Romano 14,  Annamaria Gulla 12,  Kenneth C Anderson 9,  Giorgio Inghirami 2,  Nikhil C Munshi 15,  Massimo Loda 2
Affiliations

Affiliations

  • 1 Candiolo Cancer Institute, FPO-IRCCS, Turin, Italy.
  • 2 Weill Cornell Medicine, New York, NY, United States.
  • 3 Weill Cornell Medicine, New York, New York, United States.
  • 4 Dana-Farber/Harvard Cancer Center, Boston, Massachusetts, United States.
  • 5 Weill Cornell Medical College, Sweden.
  • 6 Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
  • 7 Dana Farber Cancer Institute, Boston, MA, United States.
  • 8 Xuzhou Medical University, Xuzhou, Jiangsu, China.
  • 9 Dana-Farber Cancer Institute, Boston, MA, United States.
  • 10 Dana-Farber Cancer Institute, Harvard TH Chan School of Public Health, Boston, MA, United States.
  • 11 Magna Graecia University, Catanzaro, Italy.
  • 12 Candiolo Cancer Institute, Candiolo, Italy.
  • 13 Dana-Farber Cancer Institute, Boston, Massachusetts, United States.
  • 14 University of Catania, Catania, Italy.
  • 15 Dana-Farber Cancer Insitute, Boston, United States.
PMID: 40053701 DOI: 10.1158/1078-0432.CCR-24-2000
Abstract

Purpose: In multiple myeloma (MM), tumor cells reprogram metabolic pathways to sustain growth and monoclonal immunoglobulin production. This study examines Acetyl-CoA Carboxylase 1 (ACC1), the Enzyme driving the rate-limiting step in de novo lipogenesis (DNL), in MM metabolic reprogramming, particularly in c-Myc (MYC)-driven subtypes.

Experimental design: ACC1 expression was evaluated across MM genetic subgroups, focusing on MYC translocations. Functional studies using ACC1 inhibitors and genetic knockdown assessed MM cell growth, lipid synthesis, and metabolic homeostasis in vitro and in vivo. The role of MYC overexpression in ACC1 sensitivity was examined, with palmitate rescue experiments. Lipidomic analysis and assessments of ER stress, protein translation, and oxidative damage elucidated underlying mechanisms.

Results: ACC1 was overexpressed in MYC-translocated MM. Its inhibition or knockdown reduced MM cell growth in vitro and in vivo, particularly in MYC-overexpressing cells. ACC1 knockdown suppressed de novo lipid synthesis, partially rescued by palmitate. Lipidomic disruptions increased Cholesterol ester desaturation and altered phospholipid ratios, inducing ER stress, impaired translation, protein carbonylation, oxidative damage, and Apoptosis.

Conclusions: ACC1 is a metabolic vulnerability in MYC-driven MM. Inhibiting ACC1 disrupts lipid homeostasis, induces ER stress, and causes oxidative damage, impairing cell survival. Targeting lipid synthesis pathways, especially in MYC-dependent subtypes, offers a promising therapeutic strategy for MM.

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