Introduction
More than 90% of pancreatic cancers are pathologically classified as pancreatic ductal adenocarcinoma (PDAC). Most PDAC patients have not yet benefited from current standard treatments in terms of pathological response.
Aims & Methods
This study aimed to identify druggable targets with translational research potential on PDAC. Multimodal proteomics datasets were included, encompassing mouse PDAC cells, spheroids, organoids and tumors, as well as human PDAC organoids and tumors. Systems modeling workflow of knowledge discovery in datasets of proteomics (KDD) was used to identify the common/matched proteins between human PDAC and the research models. Multi-bioinformatics and computational molecular docking were used to identify targets and repurposed drugs.
Results
A total of 1,975 proteins characterized with degree centrality and topological coefficient were identified across the research models and patients by KDD. 32 out of 1,975 proteins were confirmed by immunohistochemistry with available antibodies in PDAC patients at the Human Protein Atlas (HPA). 3D molecular structures of the 32 proteins were obtained from the RCSB PDB and AlphaFold databases and further validated through blind docking simulations using 7,509 3D-structured ligands sourced from PubChem. The 32 protein-encoding genes included VIL1, GSN, MVB12A, SFXN2, AHNAK2, ANXA3, PACSIN2, ATP6V1F, OTUB1, SERPINB6, SNAP23, SURF1, PCCA, PLP2, ACADSB, ACTR1A, ANXA2, EIF2A, HPCAL1, MYH14, MYO1C, PCK2, PDHB, POLR2H, SCO1, SCPEP1, SH3BGRL3, SPTAN1, STAM, TIMM50, VTI1B, and YWHAQ. Of note, EIF2A had high affinity to Padnarsertib (orally small molecular drug) with -11.4 kcal/mol, whereas STAMBP had affinity to Bemcentinib (orally small molecular drugs) with -11.8 kcal/mol, and ANXA2 and AHNAK2 to Zavegepant (CGRP receptor antagonist as migraine drug) with -12.1 kcal/mol and -11.4 kcal/mol, respectively, suggesting druggable targets on endocytosis/exocytosis/phagocytosis and CGRP signaling pathways. Validation by docking network analysis (string enrichments with p<0.05 by Benjamini-Hochberg) showed that EIF2A exhibited neighborhood connectivity (Nc) at 189.72 with topological coefficient (Tn) at 0.09, whereas STAMBP was with Nc at 106.41 and Tn at 0,13, ANXA2 with Nc at 132.83 and Tn at 0.09 and AHNAK2 with Nc at 56.64 and Tn at 0.06. Specific clusters of the 32 proteins included disinhibition of SNARE formation pathway (involved machinery required for membrane fusion) (60% associated genes), negative feedback regulation of MAPK pathway (67%) and ERK/MAPK signaling pathway (involved CGRP) (100%). EIF2A, STAMBP, ANXA2 and AHNAK2 were expressed in the pancreatic ductal cells (c-6, c-12. c-13) whereas EIF2A and AHNAK2 were located in cytoplasm, STAMBP in nucleus and ANXA2 in plasma membrane according to signal cell atlas and protein-protein interactions (Ingenuity Pathway Analysis). HPA survival analysis of 176 PDAC patients with median follow-up time of 1.27 years showed that EIF2A, STAMBP, ANXA2 and AHNAK2 were strong prognostic biomarkers with p<0.001 (high expression associated with low survival probability).
Conclusion
Potential druggable targets for PDAC were identified by KDD, particularly including the key proteins with repurposed drugs acting on the ERK/MAPK signaling pathway (involved CGRP) and the membrane fusion.