Related Experiment Video
Updated: Jun 27, 2025
Assessment of the Metabolic Profile of Primary Leukemia Cells
Published on: November 21, 2018
Multiomics analysis identifies oxidative phosphorylation as a cancer vulnerability arising from myristoylation
Erwan Beauchamp1, Jay M Gamma2, Christopher R Cromwell3
1Pacylex Pharmaceuticals Inc., Edmonton, AB, Canada.
Background:
In humans, two ubiquitously expressed N-myristoyltransferases, NMT1 and NMT2, catalyze myristate transfer to proteins to facilitate membrane targeting and signaling. We investigated the expression of NMTs in numerous cancers and found that NMT2 levels are dysregulated by epigenetic suppression, particularly so in hematologic malignancies. This suggests that pharmacological inhibition of the remaining NMT1 could allow for the selective killing of these cells, sparing normal cells with both NMTs.
Methods And Results:
Transcriptomic analysis of 1200 NMT inhibitor (NMTI)-treated cancer cell lines revealed that NMTI sensitivity relates not only to NMT2 loss or NMT1 dependency, but also correlates with a myristoylation inhibition sensitivity signature comprising 54 genes (MISS-54) enriched in hematologic cancers as well as testis, brain, lung, ovary, and colon cancers. Because non-myristoylated proteins are degraded by a glycine-specific N-degron, differential proteomics revealed the major impact of abrogating NMT1 genetically using CRISPR/Cas9 in cancer cells was surprisingly to reduce mitochondrial respiratory complex I proteins rather than cell signaling proteins, some of which were also reduced, albeit to a lesser extent. Cancer cell treatments with the first-in-class NMTI PCLX-001 (zelenirstat), which is undergoing human phase 1/2a trials in advanced lymphoma and solid tumors, recapitulated these effects. The most downregulated myristoylated mitochondrial protein was NDUFAF4, a complex I assembly factor. Knockout of NDUFAF4 or in vitro cell treatment with zelenirstat resulted in loss of complex I, oxidative phosphorylation and respiration, which impacted metabolomes.
Conclusions:
Targeting of both, oxidative phosphorylation and cell signaling partly explains the lethal effects of zelenirstat in select cancer types. While the prognostic value of the sensitivity score MISS-54 remains to be validated in patients, our findings continue to warrant the clinical development of zelenirstat as cancer treatment.
Insights
N-myristoyltransferase 2 (NMT2) is epigenetically suppressed in many cancers, making cancer cells dependent on NMT1. Inhibiting NMT1 selectively kills cancer cells by disrupting mitochondrial respiration and signaling pathways.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Biology
Background:
- Two N-myristoyltransferases (NMT1 and NMT2) are essential for protein myristoylation in humans.
- NMT2 is epigenetically suppressed in various cancers, especially hematologic malignancies, creating a dependency on NMT1.
- This suggests NMT1 inhibition as a potential cancer therapy to selectively target cancer cells.
Purpose of the Study:
- To investigate the role of NMTs in cancer and identify potential therapeutic strategies.
- To explore the mechanisms by which NMT inhibitors affect cancer cells.
- To evaluate the potential of NMT inhibitors, like PCLX-001 (zelenirstat), as cancer treatments.
Main Methods:
- Transcriptomic analysis of NMT inhibitor-treated cancer cell lines.
- Differential proteomics to assess the impact of NMT1 genetic ablation.
- In vitro treatment of cancer cells with PCLX-001 (zelenirstat).
Main Results:
- NMT inhibitor sensitivity correlates with a 54-gene myristoylation inhibition sensitivity signature (MISS-54), enriched in hematologic cancers and other cancer types.
- Abrogating NMT1 primarily reduces mitochondrial respiratory complex I proteins, including NDUFAF4, impacting oxidative phosphorylation and respiration.
- PCLX-001 treatment recapitulated these effects, leading to mitochondrial dysfunction and altered metabolomes.
Conclusions:
- Targeting both oxidative phosphorylation and cell signaling contributes to the efficacy of zelenirstat in specific cancer types.
- The MISS-54 score requires further validation in patients for prognostic value.
- Findings support the continued clinical development of zelenirstat for cancer treatment.
More Related Videos
Related Concept Videos
01:46Electron Transport Chain: Complex I and II
ROS generation is regulated and maintained at moderate levels necessary...
03:03mTOR Signaling and Cancer Progression
The mTOR pathway or the...
01:22PI3K/mTOR/AKT Signaling Pathway
02:53Adaptive Mechanisms in Cancer Cells
Some of the advantages that cancer cells have on normal cells include - enhanced ability to divide without terminally differentiating, induce new blood vessel formation,...
01:45Mitochondrial Membranes