Repurposing disulfiram for ALDH-positive NSCLC: Network-based inhibition of EGFR, COX-2, and MAPK1.

The clinical management of non-small cell lung cancer (NSCLC) is of major challenge due to the contribution of ALDH-positive non-small cell lung cancer to tumor aggressiveness, metastasis, and resistance to therapy. The FDA-approved alcohol aversion agent disulfiram (DSF) has been shown to be promising in preclinical models aiming to treat tumor in the animal model but its efficacy in vivo is limited by poorly understood molecular targets in ALDH + NSCLC. Our hypothesis is that DSF will act on important nodes within the oncogenic (EGFR/MAPK), inflammatory (COX-2) and redox pathways which maintain ALDH + stemness. To evaluate this, network pharmacology was used and determined 137 common targets to exist between DSF and NSCLC-related genes. Analysis of protein-protein interaction has identified the following central hubs: EGFR, PTGS2 (COX-2), and MAPK1. These targets were found to bind DSF with very high affinity (7.45 -6.15 -6.65 kcal/mol, respectively) in comparison to reference inhibitors (Erlotinib, Celecoxib, Sorafenib). The RMSD values remaining below 2.1 Å, MMGBSA analysis, and consistent energy gyration profiles, supporting the stability of the DSF-target complexes. DSF (IC50 = 2.5 μM) experimentally caused a significant decrease in phosphorylation of EGFR, ERK1 (MAPK1) and COX-2 in NSCLC cells. The article presents mechanistic support to the multi-target effect of DSF in ALDH + NSCLC through inhibition of EGFR, COX-2, and MAPK1, potent agents of stemness and resistance to drugs. It is believed that the reuse of DSF would be effective in treating NSCLC therapeutic resistance and promote its use in practice.