Page 71 - TD-4-1

Tumor Discovery Drug repurposing for pancreatic cancer via AI

Table 3. Overview of potential multi‑molecular drugs screened for pancreatic ductal adenocarcinoma treatment based on three
drug design specifications using a systematic drug discovery approach
Target drug c‑MYC FOXO3 TP53 Sensitivity (PRISM) Toxicity (LC50, mol/kg)
MK-2206 • 0.772406631 5.561
Gemcitabine • • 2.417963872 2.381
MK-2206 Gemcitabine

Note: • Denotes drug targeting on the corresponding biomarker.
Abbreviations: FOXO3: Forkhead box O3; LC50: Lethal concentration 50%; PRISMA: Pharmaceutical Regulatory Information System; TP53: Tumor
suppressor p53.

we selected gemcitabine as a potential drug for further important to consider potential synergistic or antagonistic
evaluation. effects between the drugs, which may not have been fully
MK-2206 is an AKT inhibitor. Abnormal activation of captured in the model predictions.
the PI3K/AKT signaling pathway affects cell metabolism These limitations should be addressed in future
and survival, cell cycle progression, apoptosis regulation, research to enhance the reliability and applicability of drug
protein synthesis, and genome instability. Since the PI3K/ repurposing strategies in PDAC treatment.
69
AKT pathway is frequently dysregulated in many cancers,
MK-2206 inhibits AKT and downregulates FOXO3, 70,71 5. Conclusion
thereby exhibiting anti-tumor activity and increasing cancer In this research, we employed a systems biology approach
cell sensitivity to chemotherapy and radiotherapy. MK-2206 to construct candidate GWGENs by mining large-scale
is often used in combination with other chemotherapy databases. We then applied system identification and order
drugs to improve therapeutic efficacy. Current studies detection methods to eliminate false positive interactions
72
show that MK-2206 is well tolerated and can effectively within candidate GWGENs, thereby generating the real
block AKT signaling, making it a promising candidate for GWGENs for PDAC and healthy controls. Using the
73
repurposing as a potential drug for PDAC treatment. principal network projection method, we extracted the core
However, this study has several limitations. First, GWGENs for both PDAC and healthy controls. To elucidate
the analysis was based on GSE183795 microarray data, the oncogenic mechanisms of PDAC, we annotated the core
and the quality and completeness of this dataset directly GWGENs with KEGG pathways to identify core signaling
influence the accuracy of the results. If the dataset contains pathways in PDAC and healthy controls. By comparing the
significant noise or incomplete data, it may lead to erroneous core signal pathways between PDAC and healthy controls,
conclusions. Second, the findings of this study are primarily we investigated the association between these pathways and
based on mathematical modeling and bioinformatics downstream cellular dysfunctions in PDAC, identifying
analysis, and lack direct experimental validation. key biomarkers involved in the carcinogenesis of PDAC as
Predictions made without experimental confirmation may potential drug targets. With these drug targets, we utilized
face challenges in practical application, highlighting the a DNN-based DTI model to predict the probability of
need for further laboratory experiments to confirm the interaction between the drugs and their targets. Based on
results. While there is limited experimental research on the drug’s regulatory ability, sensitivity, and toxicity, we
the combination treatment of MK-2206 and gemcitabine, selected a potential multi-molecular drug combination.
existing studies suggest that this combination may be Ultimately, we identified MK-2206 and gemcitabine as a
effective. 74,75 Additionally, although our study predicts promising combination for PDAC treatment, targeting
multi-drug combination, the actual pharmacodynamic significant biomarkers such as c-MYC, FOXO3, and TP53,
interactions and effects of this combination need to be as shown in Table 3. While the Drug Interaction Checker
verified through in vivo and in vitro experiments. It is also suggests that there is no known interaction between these

Volume 4 Issue 1 (2025) 63 doi: 10.36922/td.4709