EGFR L858R + EGFR T790M

Autophagy inhibition by 3-methyladenine and ATG gene silencing effectively decreased the cytotoxic effect of GMI, suggesting that GMI induces autophagic cell death in H1975/TR cells. This study is the first to reveal the novel role of GMI in inducing cytotoxic effects in H1975 cells and H1975/TR cells with osimertinib resistance through two different forms of cell death: apoptosis and autophagy, respectively.

Additionally, Lazertinib's improved central nervous system (CNS) penetration enhances its therapeutic potential in patients with brain metastases. As ongoing clinical trials further elucidate its role, Lazertinib emerges as a promising next-generation EGFR inhibitor, offering a safer and more effective alternative for NSCLC treatment.

Structural studies indicate that certain hydrophobic and hydrophilic interactions are associated with L858R/T790M selectivity, offering insights into structure-guided design. These results offer a broadly applicable approach for prioritizing compounds and support the integration of kinetic and selectivity data in TCI discovery campaigns.

To resolve the underlying coordination mechanism, we apply neural relational inference to reconstruct time-dependent interaction networks, uncovering the mutation-induced rewiring of allosteric pathways linking distant regulatory regions. This coupling of conformational redistribution with network remodeling provides a mechanistic rationale for sustained EGFR activation and suggests new opportunities for targeting dynamically organized allosteric circuits in therapeutic design.

Osimertinib is currently the first-line treatment choice for patients with EGFR L858R/T790M mutations, however, as to other EGFR-TKIs, resistance inevitably occurs...TCM achieves these effects by regulating multiple signaling pathways and mechanisms, while also exhibiting synergistic interactions with EGFR tyrosine kinase inhibitors (TKIs). This review highlights the mechanisms through which TCM influences NSCLC patients harboring EGFR mutations, offering a promising therapeutic strategy for those with EGFR-TKI resistance.

The IC50 comparable to the Osimertinib - one of the most renowned EGFR-TKIs - emphasizes the remarkable success of the design approach...Kinetic studies, molecular modeling, and Plasmon Internal Reflection Surface-Enhanced Infrared Absorption (PIR-SEIRA) microscopy suggests that FL30 binds to the orthosteric site while inducing the transition of the mutant EGFR toward an inactive-like state. These findings highlight FL30's potential for further optimization and propose a novel approach for developing targeted therapies that combine orthosteric binding with allosteric modulation.

Erlotinib and Doxorubicin served as the reference drugs. To further validate these findings, docking simulations of the promising derivatives 7i and 7f were conducted to assess their anticipated binding affinities with EGFR and its T790M/L858R mutants. Thus, compound 7f has the potential to be developed into a potent anticancer agent.

Most prominent alterations were observed in EGFR (auto-phosphorylation Y1197 and 10 bi- and triantennary fucosyl-sialo glycans at N603), downstream PI3K-Akt pathway (ERBB2-T1240, MET-S990/T992, AKT-S124/S126) and integrin family (sialo-fucosyl glycans), suggesting site-specific alteration between N-glycosylation and phosphorylation interplay in the TKI resistant L858R-T790M mutant NSCLC cells. The glycoproteomic and phosphoproteomic landscape may help to unravel the complex modification alterations underlying the resistant mechanism, offering insights for improving therapeutic strategies and patient outcomes.

Furthermore, Piperlongumine significantly inhibited tumor growth in both Osimertinib-sensitive and resistant NSCLC xenograft models. These findings highlight the potential of Piperlongumine as an effective agent in overcoming EGFR-targeted therapy resistance and suggest new avenues for its clinical application in NSCLC treatment.

Recently, fourth-generation AIs, EAI045, have been discovered to potently and selectively inhibit various EGFR mutations but limited antiproliferative effects in the absence of the antibody cetuximab...However, path-independent alchemical approaches like streamlined alchemical free energy perturbation and binding free energy estimator 2 (BFEE2) were employed to validate the results and identify potent compounds. These findings pave the way to identification of novel potential fourth-generation AIs, which require further experimental validation.

Erlotinib (ERL) is a first-line targeted therapy for patients with epidermal growth factor receptor (EGFR)-mutant advanced non-small cell lung cancer (NSCLC)...Upon endocytosis and interaction with overexpressed GSH in A549 cells, the disulfide-bond linker is cleaved to release three components: ERL, UA (which downregulates β-catenin/TCF4/CT45A2 signaling pathways, inducing apoptosis in ERL-resistant L858R/T790M mutant cells-a key factor in acquired resistance to ERL treatment), and QM-OH. Hence, this work provides a universal model for multifunctional NSCLC therapy that effectively addresses ERL resistance while enhancing cytotoxicity and biocompatibility.

The establishment of tumoroids from lung cancer cell lines is feasible with various methodologies, which is promising for future tumoroid growth from clinical lung cancer samples. However, analysis of relevant markers is a prerequisite and may need to be validated for each model and cell type.