Computational Methods for the Analysis and Prediction of EGFR-Mutated Lung Cancer Drug Resistance: Recent Advances in Drug Design, Challenges and Future Prospects

Lung cancer is a major cause of cancer deaths worldwide, and has a very low survival rate. Non-small cell lung cancer (NSCLC) is the largest subset of lung cancers, which accounts for about 85% of all cases. It has been well established that a mutation in the epidermal growth factor receptor (EGFR) can lead to lung cancer. EGFR Tyrosine Kinase Inhibitors (TKIs) are developed to target the kinase domain of EGFR. These TKIs produce promising results at the initial stage of therapy, but the efficacy becomes limited due to the development of drug resistance. In this paper, we provide a comprehensive overview of computational methods, for understanding drug resistance mechanisms. The important EGFR mutants and the different generations of EGFR-TKIs, with the survival and response rates are discussed. Next, we evaluate the role of important EGFR parameters in drug resistance mechanism, including structural dynamics, hydrogen bonds, stability, dimerization, binding free energies, and signaling pathways. Personalized drug resistance prediction models, drug response curve, drug synergy, and other data-driven methods are also discussed. Recent advancements in deep learning; such as AlphaFold2, deep generative models, big data analytics, and the applications of statistics and permutation are also highlighted. We explore limitations in the current methodologies, and discuss strategies to overcome them. We believe this review will serve as a reference for researchers; to apply computational techniques for precision medicine, analyzing structures of protein-drug complexes, drug discovery, and understanding the drug response and resistance mechanisms in lung cancer patients.