Breast Cancer Drug Neratinib Found to Protect Against Atherosclerosis
American Heart Month
Atherosclerosis is a common disease that develops when the buildup of fats, cholesterol and other substances in and on the artery walls. This buildup—called plaque—can cause arteries to narrow, blocking blood flow or even burst, resulting in a blood clot. Heart diseases linked to atherosclerosis, or atherosclerotic cardiovascular disease (ASCVD), remains the leading cause of morbidity and mortality globally.
Heart Month is a time to raise awareness about heart health and reduce the risk of heart disease. Fortunately, most people can prevent or delay atherosclerosis development through heart-healthy living and mitigating risk factors of heart disease. Cholesterol-lowering drugs (such as statins and PCSK9 inhibitors) can also be used to treat patients with ASCVD. While these treatments effectively reduce plaque buildup, they do not directly address the persistent inflammation that drives atherosclerosis. The release of inflammatory factors like TNF-α, IL-1β, and IL-6 by vascular cells contribute to disease progression, which still leaves patients at risk for adverse cardiovascular events.
The Role of Breast Cancer Drug Neratinib in Atheroprotection
Emerging preclinical and clinical evidence suggests that targeting inflammation can reduce cardiovascular risk, which has led researchers to examine anti-inflammatory therapies as a potential complement to standard lipid-lowering treatments to treat ASCVD. Instead of new drug discovery, drug repurposing is a strategic approach that can be applied to accelerate the identification of effective inflammation-targeted therapies. Repurposing FDA-approved drugs for new indications helps mitigate the high costs, failure rates, and long development timelines.
In a new publication, Zhang and colleagues used in silico Connectivity Map (CMap) exploration and cell-based experiments to identify FDA-approved hit compounds that can also effectively treat endothelial inflammation. To identify the shared inflammatory gene signature involved in endothelial cell inflammation, Lifeline® Cell Technology human umbilical vein endothelial cells (HUVECs) were stimulated with inflammatory stimuli TNF-α or IL-1β, known drivers of endothelial inflammation. Transcriptomic RNA sequencing was then used to select the top 150 up- and down-regulated genes for CMap analysis.
CMap screening identified Neratinib, a clinical drug against breast cancer, as the hit compound with potential anti-inflammatory actions in endothelial cells. Neratinib is a small-molecule tyrosine kinase inhibitor that irreversibly inhibits the activation of human epidermal growth factors (HER1/EGFR, HER2/ERBB2, and HER4/ERBB4). HER2, encoded by ERBB2, is the classical target of Neratinib.
Next, the anti-inflammatory effect of Neratinib was evaluated in HUVECs. Neratinib was able to inhibit endothelial cell inflammation elicited by three different pro-inflammatory stimuli (TNFα, IL-1β and LPS). In the Ldlr-/- mouse model, Neratinib was also able to protect against atherosclerosis progression as evidenced by a reduction in the number and size of plaques. Mechanistically, Neratinib’s anti-inflammatory effects were found to be independent of its classical target HER2/ERBB2 inhibition. Transcriptome profiling in Neratinib-treated HUVECs in the presence of TNF-α revealed that Neratinib directly binds the ATP domain of ASK1, suppressing its activation.
Taken together, these results demonstrate Neratinib protects against atherosclerosis by reducing endothelial inflammation via ASK1 inhibition. As a repurposed drug, Neratinib holds promise to address residual inflammatory risk in ASCVD and complement existing lipid-lowering therapies.
Lifeline Cell Technology Endothelial and Cardiac Cells
Lifeline Cell Technology has a large portfolio of primary endothelial and cardiac cells to power your cardiovascular disease research:
- Cardiac microvascular endothelial cells
- Cardiac fibroblasts
- Pulmonary artery endothelial cells
- Aortic endothelial cells
- Coronary artery endothelial cells
- Lung microvascular endothelial cells
- Dermal microvascular endothelial cells (adultand neonatal)
- Iliac artery endothelial cells
- Umbilical cord endothelial cells (HUVECs; primaryand 10-donor pool)
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