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

TitleTargeting Acetyl-CoA Carboxylase Suppresses De Novo Lipogenesis and Tumor Cell Growth in Multiple Myeloma.
Publication TypeJournal Article
Year of Publication2025
AuthorsMorelli E, Ribeiro CFidalgo, Rodrigues SD, Gao C, Socciarelli F, Maisano D, Favasuli V, Liu N, Todoerti K, Chakraborty C, Yao Y, Fulciniti M, Samur M, Aktas-Samur A, Amodio N, Turi M, Barello F, Penailillo J, Giallongo C, Romano A, Gulla A, Anderson KC, Inghirami G, Munshi NC, Loda M
JournalClin Cancer Res
Volume31
Issue10
Pagination1975-1987
Date Published2025 May 15
ISSN1557-3265
KeywordsAcetyl-CoA Carboxylase, Animals, Cell Line, Tumor, Cell Proliferation, Endoplasmic Reticulum Stress, Gene Expression Regulation, Neoplastic, Humans, Lipogenesis, Mice, Multiple Myeloma, Proto-Oncogene Proteins c-myc, Xenograft Model Antitumor Assays
Abstract

PURPOSE: In multiple myeloma, 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, in multiple myeloma metabolic reprogramming, particularly in c-MYC (MYC)-driven subtypes.

EXPERIMENTAL DESIGN: ACC1 expression was evaluated across multiple myeloma genetic subgroups, focusing on MYC translocations. Functional studies using ACC1 inhibitors and genetic knockdown assessed multiple myeloma 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 endoplasmic reticulum (ER) stress, protein translation, and oxidative damage elucidated underlying mechanisms.

RESULTS: ACC1 was overexpressed in MYC-translocated multiple myeloma. Its inhibition or knockdown reduced multiple myeloma 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 multiple myeloma. 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 multiple myeloma.

DOI10.1158/1078-0432.CCR-24-2000
Alternate JournalClin Cancer Res
PubMed ID40053701
PubMed Central IDPMC12081190
Grant List / / Paula and Rodger Riney Foundation /
T32CA260293 / / Weill Cornell Medicine (WCM) /
/ / Leukemia and Lymphoma Society (LLS) /
CA207237-05 / / Center for Cancer Research (CCR) /
/ / Italian Ministry of Health /
#27750 / / Italian Association for Cancer Research (AIRC) /
/ / American Society of Hematology (ASH) /
2022CHAL05 / / Prostate Cancer Foundation (PCF) /
P50 CA211024 / CA / NCI NIH HHS / United States
/ / International Myeloma Society (IMS) /
/ / FPRC "5xmille" 2021 Ministry of Health project (EMAGEN-LongMynd) /
/ / International Myeloma Foundation (IMF) /
/ / FPRC "5xmille" 2019 Ministry of Health project (IDEE) /
BX001584-09 / / U.S. Department of Veterans Affairs (VA) /
SPORE-P50CA100707 / / Dana Farber/Harvard Cancer Center SPORE in Multiple Myeloma /
IG24449 / / Italian Association for Cancer Research (AIRC) /
P01 CA265768 / CA / NCI NIH HHS / United States
CA155258-10 / / National Cancer Institute (NCI) /
#29106 / / Italian Association for Cancer Research (AIRC) /
P50CA211024 / / Weill Cornell Medicine (WCM) prostate cancer SPORE /
W81XWH-19-1-0566 / / U.S. Department of Defense (DOD) /