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Molecular Characterization and Clinical Outcomes of Pancreatic Neuroendocrine Neoplasms Harboring PAK4-NAMPT
Ibrahim Azar1,2, Husain Yar Khan2,3, Sahar F Bannoura3
1IHA Hematology Oncology, Pontiac, MI.
Purpose:
The mammalian target of rapamycin (mTOR) inhibitor everolimus is US Food and Drug Administration-approved for advanced pancreatic neuroendocrine neoplasms (pNENs), yet resistance is common, necessitating the identification of resistance mechanisms for effective treatment strategies. Previous studies suggest that targeting the aberrant expression of mTOR regulators p21-activated kinase 4 (PAK4) and nicotinamide phosphoribosyl transferase (NAMPT) sensitizes pNENs to everolimus. In this study, we queried a large real-world data set of pNENs, characterizing the molecular and immune landscapes, as well as the clinical outcomes associated with aberrant PAK4 and NAMPT expression.
Methods:
Two-hundred and ninety-four pNEN cases were analyzed using next-generation sequencing and whole-exome/whole-transcriptome sequencing. We stratified patients into clusters on the basis of median cutoff.
Results:
High expression of genes activated in response to mTOR activation was found in NAMPT-high and PAK4-high groups. Enrichment of PI3K/AKT/mTOR and glycolysis pathways was observed in these tumors. Higher mutation rates in multiple endocrine neoplasia type 1, alpha thalassemia/mental retardation syndrome X-linked, TSC2, SETD2, and CCNE1 were observed in high NAMPT and PAK4 clusters. Immune analysis revealed enrichment in inflammatory response pathways, IL2/STAT5 signaling, and immune checkpoint genes. Increased neutrophils, natural killer cells, and macrophages were found in PAK4-high/NAMPT-high tumors. Analysis of real-world patient data revealed that high PAK4 (P = .0428) or NAMPT (P = .0002) expression individually correlated with lower overall survival in all neuroendocrine neoplasms (NEN) cohorts, while the combined high expression of both was associated with the worst outcomes (P = .0002). Similar trends were observed in pancreatic NEN cohorts.
Conclusion:
Our study demonstrates that PAK4-high/NAMPT-high pNENs are associated with distinct molecular and immune profiles. Further investigation is warranted to determine if dual PAK4 and NAMPT blockade enhances the efficacy of immunotherapeutics.
Insights
High expression of p21-activated kinase 4 (PAK4) and nicotinamide phosphoribosyl transferase (NAMPT) correlates with poor outcomes in pancreatic neuroendocrine neoplasms (pNENs). Targeting both PAK4 and NAMPT may improve treatment efficacy for pNENs.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Everolimus, an mTOR inhibitor, is approved for advanced pancreatic neuroendocrine neoplasms (pNENs) but resistance is common.
- Aberrant expression of p21-activated kinase 4 (PAK4) and nicotinamide phosphoribosyl transferase (NAMPT) may drive resistance to everolimus in pNENs.
Purpose of the Study:
- To characterize the molecular and immune landscapes of pNENs with aberrant PAK4 and NAMPT expression.
- To investigate the clinical outcomes associated with PAK4 and NAMPT expression in pNENs using real-world data.
Main Methods:
- Analysis of 294 pNEN cases using next-generation sequencing and whole-exome/whole-transcriptome sequencing.
- Stratification of patients into clusters based on median cutoff for PAK4 and NAMPT expression.
- Correlation analysis of gene expression, mutation rates, immune cell infiltration, and clinical outcomes.
Main Results:
- PAK4-high and NAMPT-high pNENs showed enrichment in mTOR activation, PI3K/AKT/mTOR, and glycolysis pathways.
- Higher mutation rates in key genes (e.g., MEN1, TSC2) were observed in high PAK4/NAMPT clusters.
- High PAK4 or NAMPT expression correlated with lower overall survival in NEN and pNEN cohorts, with combined high expression showing the worst outcomes.
Conclusions:
- PAK4-high/NAMPT-high pNENs exhibit distinct molecular and immune profiles.
- Dual blockade of PAK4 and NAMPT may represent a potential therapeutic strategy to enhance the efficacy of immunotherapeutics in pNENs.
