Study: Dysregulated lipid synthesis by oncogenic IDH1 mutation is a targetable synthetic lethal vulnerability Journal Cancer Discovery, Dec 2022
Overview:
Many are promoting a ketogenic diet as a panacea for cancer. This study points to the opposite — a low-fat diet may be key for cancers with specific IDH1 mutations.
The researchers looked at Isocitrate dehydrogenase 1 (IDH1), which is often mutated in several types of cancer, including AML (acute myeloid leukemia). The mutation then switched the cancerous cells (in vitro) to utilizing beta-oxidation of fatty acids.
From the study: “Cancer cells have a fundamental requirement for cellular building blocks, including lipids, to support their continuous proliferation, and metabolic reprograming for this purpose is a well-established hallmark of cancer. Whereas normal cells obtain the bulk of their lipid requirement directly from the circulation, many cancer cells synthesize a significant proportion of lipid de novo, for reasons that are not entirely clear. De novo fatty acid biosynthesis in mammals is mediated by two related enzymes; ACC1 (the product of ACACA or ACC1 gene) and ACC2 (ACACB or ACC2), which catalyze the ATP-dependent carboxylation of acetyl-coenzyme A (acetyl CoA) to form malonyl CoA. ACC1 is a dimeric cytoplasmic enzyme that controls fatty acid synthesis and is inhibited by activation of AMP-activated protein kinase (AMPK) in energy deficient states, whereas ACC2 is tethered to the mitochondrial outer membrane for localized malonyl CoA production, which regulates fatty acid oxidation. The rate limiting step in de novo lipid synthesis is accepted to be the conversion of acetyl CoA into malonyl CoA by ACC1 in the cytoplasm and in sterol-depleted conditions, IDH1 gene transcription is upregulated by sterol-regulatory element binding proteins, suggesting IDH1 regulates lipogenesis.”
The researchers tested a lipid-free diet and found that it impaired the growth of IDH1-mutant leukemia cells (in mice).
Here’s a good interview with the researchers: https://thenewdaily.com.au/life/wellbeing/2022/12/25/a-low-fat-diet-slows-tumours/