Abstract 377P
Background
Non-small cell lung cancer (NSCLC) progresses through several molecular mechanisms, including glycosylation. Overexpressed heparan sulfate, structurally similar to heparin, supports tumour growth, while glycosylated PD-L1 impairs immune checkpoint inhibitors like Atezolizumab, Avelumab, and Durvalumab. The enzyme GNPDA1 (Glucosamine-6-phosphate deaminase 1) plays a key role in the hexosamine biosynthesis pathway, which is crucial for glycosylation. Additionally, furin activates MET and IGF1, promoting tumour survival via the STAT3 and mTOR pathways. Objectives: To investigate furin-heparin interactions and develop a GNPDA1 (Glucosamine-6-phosphate deaminase 1) inhibitor to block glycosylation and inhibit tumour growth.
Methods
In silico simulations using AI-based tools explored furin-heparin interactions. Molecular docking assessed the efficacy of the GNPDA1 inhibitor.
Results
Furin-heparin interactions were observed, highlighting furin’s involvement in activating proteins, such as MET and IGF1, contributing to tumour progression. Higher levels of heparan sulfate may enhance the activation of these proteins by furin, further promoting tumour survival and growth. The GNPDA1 inhibitor effectively blocked glycosylation, reducing tumour growth and restoring the efficacy of immune therapies by limiting PD-L1 glycosylation. This inhibition allows immune checkpoint inhibitors, such as Atezolizumab, Avelumab, and Durvalumab, to regain their ability to target PD-L1, improving overall responsiveness to treatment.
Conclusions
This study underscores furin’s pivotal role in NSCLC progression and highlights GNPDA1 inhibition as a promising strategy to enhance immunotherapy and suppress tumour growth. Further in vitro and in vivo studies are needed to validate these findings.
Legal entity responsible for the study
R. da Silva Ferreira.
Funding
Has not received any funding
Disclosure
The author has declared no conflicts of interest.