Highlights in Cancer Research: August 2023

The EACR’s ‘Highlights in Cancer Research’ is a regular summary of the most interesting and impactful recent papers in cancer research, curated by the Board of the European Association for Cancer Research (EACR).

The list below appears in no particular order, and the summary information has been provided by the authors unless otherwise indicated.

Use the dropdown menu or ‘Previous’ and ‘Next’ buttons to navigate the list.

2. Dysregulated Lipid Synthesis by Oncogenic IDH1 Mutation Is a Targetable Synthetic Lethal Vulnerability

Thomas, D. et al. Cancer Discovery. 13 (2): 496–515 (2023).
doi: 10.1158/2159-8290.CD-21-0218.

Summary of the findings

The genes encoding isocitrate dehydrogenase 1 and 2 (IDH1/2) are mutated in multiple cancers and drive the production of the oncometabolite (R)-2-hydroxyglutarate (R-2HG). However, specific differences between these two mutations with targetable implications have not been described. In the paper by Thomas et al, we discover a novel susceptibility specifically for IDH1 mutation (mIDH1) by identifying the lipid synthesis enzyme ACC1 (acetyl CoA carboxylase 1) as a synthetic lethal target. By analyzing the metabolome of primary acute myeloid leukaemia (AML) blasts, we identified a mIDH1-specific reduction in fatty acids compared to healthy progenitor cells that was not observed in IDH2-mutant AML. Moreover, mIDH1 cells exhibited an increase in acyl-carnitine linked fatty acids destined for the mitochondria, indicating a switch to beta-oxidation. Overall, our data show that mIDH1 cancer cells have a higher dependency on both exogenous and de novo fatty acids than mIDH2 AML. This suggests that differences in intracellular localization between cytoplasmic IDH1 and mitochondrial IDH2 can have profound effects on metabolic phenotypes. Strikingly, mIDH1 AML cells exhibited a defect in reductive carboxylation involved in de novo lipid synthesis, which was not reversible by the mIDH1-specific inhibitor ivosidenib, suggesting this defect is R-2HG independent, and nominating a mechanism for the mIDH1 specificity. In xenograft models, a lipid-free diet markedly slowed the growth of mIDH1 AML, but not healthy CD34+ stem and progenitor cells or IDH2-mutant AML suggesting the potential for precision dietary modification for IDH1-mutant cancers. Genetic and pharmacologic targeting of ACC1 resulted in growth inhibition of mIDH1 cancers, again not reversible by ivosidenib. Finally, pharmacologic targeting of ACC1 with ND-646, an ACC1-selective inhibitor, improved sensitivity of mIDH1 AML to venetoclax, a BH3 mimetic which is the current standard of care for older patients with AML.

Future impact

This paper is important because it demonstrates novel targets for IDH1 mutant cancers beyond the production of the oncometabolite (R)-2-hydroxyglutarate, and offers new insights for designing an ultra-precision approach encompassing diet and targeted therapy for cancer patients with IDH1, but not IDH2, mutant cancers. This is clinically relevant because emerging results from clinical trials testing mutant IDH inhibitors, such as ivosidenib, do not always result in tumour regression despite marked decreases in the oncometabolite. The pre-clinical data presented here suggests some patients with IDH1 mutant cancers, including AML in remission, cholangiocarcinoma, oligodendroglioma, and chondrosarcoma may benefit from general lipid-lowering and/or a lipid-free diet. This paper suggests other metabolic dependencies beyond the Warburg effect, depending on somatic mutation context, such as mitochondrial-driven beta oxidation are also involved in cancer metabolism. This paper reinforces other recent studies supporting the notion that many cancers are not dependent on ATP or carbon supply for growth, but are desperate for an adequate supply of re-usable NADPH (via NADH) and are prepared to sacrifice both de novo and exogenous fatty acids to guarantee this. Several new targets based on this work (AMPK, NAD kinase, beta-oxidation enzymes) deserved to be explored in future studies in both AML and other solid tumour models, contrasting IDH1 with IDH2.

Read more in Cancer Discovery