bms-599626 and Lung-Neoplasms

Epidermal growth factor receptor (EGFR) is of great significance in mediating cell signaling transduction and tumor behaviors. Currently, third-generation inhibitors of EGFR, especially osimertinib, are at the clinical frontier for the treatment of EGFR-mutant non-small-cell lung cancer (NSCLC). Regrettably, the rapidly developing drug resistance caused by EGFR mutations and the compensatory mechanism have largely limited their clinical efficacy. Given the synergistic effect between EGFR and other compensatory targets during tumorigenesis and tumor development, EGFR dual-target inhibitors are promising for their reduced risk of drug resistance, higher efficacy, lower dosage, and fewer adverse events than those of single-target inhibitors. Hence, we present the synergistic mechanism underlying the role of EGFR dual-target inhibitors against drug resistance, their structure-activity relationships, and their therapeutic potential. Most importantly, we emphasize the optimal target combinations and design strategies for EGFR dual-target inhibitors and provide some perspectives on new challenges and future directions in this field.

Topics: Aniline Compounds; Carcinoma, Non-Small-Cell Lung; Drug Resistance, Neoplasm; ErbB Receptors; Humans; Lung Neoplasms; Mutation; Protein Kinase Inhibitors

Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cytokines; Drug Discovery; fms-Like Tyrosine Kinase 3; Humans; Leukemia, Myeloid, Acute; Lung Neoplasms; Mice; Molecular Targeted Therapy; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Proteomics; Xenograft Model Antitumor Assays