Related Experiment Video
Updated: Jun 20, 2025
Author Spotlight: Advancements in Molecular Biomarker Testing for Non-Squamous Non-Small Cell Lung Cancer
Published on: September 8, 2023
Genomic and computational-aided integrative drug repositioning strategy for EGFR and ROS1 mutated NSCLC
Varsha Tripathi1, Aishwarya Khare1, Divyanshi Shukla2
1Department of Biochemistry, Dr. Ram Manohar Lohia Avadh University Ayodhya, Uttar Pradesh, India.
Abstract:
Non-small cell lung cancer (NSCLC) has been marked as the major cause of death in lung cancer patients. Due to tumor heterogeneity, mutation burden, and emerging resistance against the available therapies in NSCLC, it has been posing potential challenges in the therapy development. Hence, identification of cancer-driving mutations and their effective inhibition have been advocated as a potential approach in NSCLC treatment. Thereof, this study aims to employ the genomic and computational-aided integrative drug repositioning strategy to identify the potential mutations in the selected molecular targets and repurpose FDA-approved drugs against them. Accordingly, molecular targets and their mutations, i.e., EGFR (V843L, L858R, L861Q, and P1019L) and ROS1 (G1969E, F2046Y, Y2092C, and V2144I), were identified based on TCGA dataset analysis. Following, virtual screening and redocking analysis, Elbasvir, Ledipasvir, and Lomitapide drugs for EGFR mutants (>-10.8 kcal/mol) while Indinavir, Ledipasvir, Lomitapide, Monteleukast, and Isavuconazonium for ROS1 mutants (>-8.8 kcal/mol) were found as putative inhibitors. Furthermore, classical molecular dynamics simulation and endpoint binding energy calculation support the considerable stability of the selected docked complexes aided by substantial hydrogen bonding and hydrophobic interactions in comparison to the respective control complexes. Conclusively, the repositioned FDA-approved drugs might be beneficial alone or in synergy to overcome acquired resistance to EGFR and ROS1-positive lung cancers.
Insights
This study identifies new drug targets for non-small cell lung cancer (NSCLC) by analyzing mutations in EGFR and ROS1. Repurposed FDA-approved drugs show promise in overcoming resistance to current NSCLC therapies.
Area of Science:
- Oncology
- Pharmacology
- Computational Biology
Background:
- Non-small cell lung cancer (NSCLC) remains a leading cause of cancer mortality.
- Tumor heterogeneity and acquired resistance present significant challenges in NSCLC treatment development.
- Targeting cancer-driving mutations is a crucial strategy for effective NSCLC therapy.
Purpose of the Study:
- To identify potential mutations in EGFR and ROS1 molecular targets within NSCLC.
- To repurpose FDA-approved drugs against identified mutations using a computational drug repositioning strategy.
- To evaluate the efficacy of repurposed drugs in overcoming resistance in EGFR and ROS1-positive NSCLC.
Main Methods:
- Genomic data analysis using TCGA dataset to identify EGFR and ROS1 mutations.
- Virtual screening and redocking analysis to identify potential drug candidates.
- Molecular dynamics simulations and binding energy calculations to assess complex stability.
Main Results:
- Identified key mutations in EGFR (V843L, L858R, L861Q, P1019L) and ROS1 (G1969E, F2046Y, Y2092C, V2144I).
- Discovered potential inhibitors: Elbasvir, Ledipasvir, Lomitapide for EGFR mutants; Indinavir, Ledipasvir, Lomitapide, Monteleukast, Isavuconazonium for ROS1 mutants.
- Molecular dynamics simulations confirmed the stability and significant interactions of docked drug-target complexes.
Conclusions:
- Repurposed FDA-approved drugs demonstrate potential as novel therapeutic agents for NSCLC.
- These drugs may be effective alone or in combination to combat acquired resistance in EGFR and ROS1-positive NSCLC.
- The study provides a foundation for developing new treatment strategies against challenging NSCLC mutations.
