Repurposing Non-Nucleosidic Reverse Transcriptase Inhibitors (NNRTIs) to Overcome EGFR T790M-Mediated Acquired Resistance in Non-Small Cell Lung Cancer.

Abstract

This study investigates the repurposing potential of non-nucleosidic reverse transcriptase inhibitors (NNRTIs), specifically Rilpivirine and Etravirine, as L858R/T790M tyrosine kinase inhibitors for addressing acquired resistance in non-small cell lung cancer (NSCLC). Using in silico molecular docking, Rilpivirine demonstrated a docking score of -7.534 kcal/mol, comparable to established epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) like Osimertinib and WZ4002. Molecular dynamics (MD) simulations over 200 ns revealed the stability of the Rilpivirine-EGFR complex, with RMSD values ranging from 2.5 to 3.5 Å. The in vitro antiproliferative assays showed that Rilpivirine had an IC₅₀ value of 2.3 µM against H1975 cells, while WZ4002 had an IC₅₀ of 0.291 µM, indicating moderate efficacy. Enzymatic assays revealed that Rilpivirine inhibited the double mutant epidermal growth factor receptor tyrosine kinase (EGFR TK) with an IC₅₀ value of 54.22 nM and spared the wild-type EGFR TK with an IC₅₀ of 22.52 nM. These findings suggest Rilpivirine's potential as a therapeutic agent for NSCLC with EGFR L858R/T790M mutations.