gefitinib

A virtual cohort of 1,000 patients with advanced EGFR-mutant NSCLC received osimertinib (80 mg daily) or comparator first-line EGFR-tyrosine kinase inhibitors (gefitinib/erlotinib). Probabilistic analyses confirmed PMX superiority across willingness-to-pay thresholds. Pharmacometric models, enabling individualized dosing and exposure-driven effects, provide more biologically plausible estimates, supporting their integration into HTAs for precision oncology.

When combined with EGFR inhibitors (osimertinib and gefitinib) in PC9 cells, the mimics showed a higher rate of growth inhibition compared with the controls and reduced IC50 values. Similarly, conmiR-15/107 enhanced growth inhibition by the KRAS inhibitors sotorasib and adagrasib in H358 cells...Long-term assays showed that the mimics reduced the survival and delayed the proliferation of DTPs in osimertinib-treated PC9 cells as well as sotorasib-treated H358 cells. These findings support conmiR-15/107 as a potential adjunct to targeted therapy, capable of enhancing treatment efficacy and delaying resistance in lung adenocarcinoma.

Pharmacologic inhibition studies were conducted using the epidermal growth factor receptor (EGFR) inhibitor gefitinib to validate mechanistic links...These findings identify a previously unrecognized anti-tumor mechanism of KSM through inhibition of CHI3L1-EGFR-STAT3 signaling and suppression of M2-like TAM differentiation. KSM may therefore represent a promising immunomodulatory strategy for treating melanoma lung metastasis and other CHI3L1-driven malignancies.

Co-administration of YFSJ and gefitinib suppresses the growth and migration of NSCLC. ANKRD1 may be a potential biomarker for EGFR exon 20 mutation-driven resistance. This therapy reduces resistance to first-generation EGFR-TKIs by blocking YAP/ANKRD1 axis to suppress cell proliferation and promoting apoptosis. Based on our previous clinical investigations and the present preclinical findings, YFSJ-particularly in combination with gefitinib-may represent a novel therapeutic strategy and warrants further exploration for the treatment of NSCLC resistant to EGFR exon 20 mutations.

A focused translational approach that combines structural insights with innovative therapeutic strategies is urgently needed to achieve lasting clinical benefits in EGFR-driven cancers.

First-line treatment with the tyrosine kinase inhibitor afatinib was associated with improved OS compared with that of patients treated with erotinib or gefitinib. In addition, combination therapy with the angiogenesis inhibitor bevacizumab had a positive impact on OS...These findings highlight the importance of molecular profiling and individualized treatment strategies in optimizing OS for patients with advanced lung adenocarcinoma. Furthermore, the validated machine learning models may serve as useful tools for risk stratification and personalized prognostic assessment to support clinical decision-making.

P2, N=45, Recruiting, Memorial Sloan Kettering Cancer Center

In vitro experiments using PC-9 cells included Cell Counting Kit-8 (CCK-8) assays (cell viability), wound healing assays (migration), flow cytometry (apoptosis/cell cycle), RNA sequencing (RNA-seq), public transcriptome datasets (GSE193258, GSE178975) were analyzed to compare ETS variant transcription factor 4 (ETV4) expression across EGFR-TKIs (aumolertinib, osimertinib, and gefitinib). ETV4 knockdown enhanced aumolertinib-induced apoptosis/G2/M arrest in vitro and synergistically suppressed tumor growth in vivo. These findings revealed that ETV4 enhanced the therapeutic efficacy of aumolertinib in vitro and in vivo, indicating that ETV4 is a potential therapeutic co-target, serving as a treatment strategy to prevent the acquired resistance induced by aumolertinib.

P1, N=94, Not yet recruiting, Fuzhou General Hospital

The CDK2 inhibitory evaluation of pyrazolo[3,4-b]pyridines 6a-g and 7a-f revealed that compounds 6e, 7b, and 7c exhibited potent inhibition (IC₅₀ = 0.88, 1.89, and 1.23 μM, respectively), compared to roscovitine (IC₅₀ = 0.84 μM). Among the spiro-oxindole derivatives 8a-d, compounds 8b and 8c demonstrated remarkable EGFR inhibition (IC₅₀ = 0.13 and 0.09 μM, respectively) and significant activity against mutant EGFRT790M (IC₅₀ = 0.32 and 0.14 μM) relative to gefitinib (IC₅₀ = 0.03 and 0.18 μM, respectively)...Molecular docking studies combined with molecular dynamics simulations further supported stable ligand-protein interactions within CDK2, EGFR, and mutant EGFRT790M active sites, with favorable binding energies and conformational stability throughout 100 ns trajectories. Collectively, these findings identify compounds 6e and 8c as promising lead scaffolds for further development of CDK2 or EGFR inhibitors with potent and selective anticancer properties.

Among these, JS04 emerged as the most potent derivative, exhibiting antiproliferative activity with IC₅₀ values of 8.11 ± 0.43 μM and 11.58 ± 1.68 μM against H1975 (EGFR-TKI resistant) and A549 (EGFR-independent) cell lines, respectively, outperforming gefitinib. Real-time impedance (xCELLigence) and flow cytometry analyses demonstrated that JS04 induced rapid, dose-dependent apoptosis, achieving 74% apoptotic cell death at 20 μM, substantially higher than erlotinib (13%). Proteome profiling confirmed activation of both intrinsic (downregulation of Bcl-2, Bcl-xL, and survivin) and extrinsic (upregulation of TRAIL R2/D5) apoptotic pathways, accompanied by G₂/M phase cell cycle arrest comparable to osimertinib...Computational studies, molecular docking and 100 ns molecular dynamics simulations indicated that JS04 forms stable hydrogen bonds with hinge region residues MET793 and GLN791, and exhibits strong binding affinity toward the EGFRL858R/T790M kinase. Collectively, these findings position JS04 as a promising quinazoline-based lead candidate that effectively triggers dual apoptotic mechanisms, selectivity toward H1975 cells, and demonstrates early indications of safety, warranting further biochemical validation, structure-activity optimisation, and in vivo efficacy evaluation.

NSCLC-BM showed higher genomic biomarker enrichment (80% vs. 68.68%) but poorer outcomes than mNSCLC. EGFR was the most common targetable mutation, followed by ALK in NSCLC-BM and KRAS in mNSCLC.