bms-777607 and Carcinoma--Non-Small-Cell-Lung

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

Tyrosine kinase inhibitors (TKIs) of the EGF receptor (EGFR) have provided a significant improvement in the disease outcome of nonsmall cell lung cancer (NSCLC). Unfortunately, resistance to these agents frequently occurs, and it is often related to the activation of the Hedgehog (Hh) and MET signaling cascades driving the epithelial-to-mesenchymal transition (EMT). Because the concomitant inhibition of both Hh and MET pathways restores the sensitivity to anti-EGFR drugs, here we aimed at discovering the first compounds that block simultaneously MET and SMO. By using an "in silico drug repurposing" approach and by validating our predictions both in vitro and in vivo, we identified a set of compounds with the desired dual inhibitory activity and enhanced antiproliferative activity on EGFR TKI-resistant NSCLC. The identification of the known MET TKIs, glesatinib and foretinib, as negative modulators of the Hh pathway, widens their application in the context of NSCLC.

Topics: Animals; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Drug Repositioning; Drug Resistance, Neoplasm; ErbB Receptors; Female; HEK293 Cells; Humans; Lung; Lung Neoplasms; Mice, Inbred BALB C; Mice, Nude; Molecular Docking Simulation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Smoothened Receptor

The epidermal growth factor receptor (EGFR) family has been well-known for more than ten years as the target of non-small lung carcinoma (NSCLC) which is one of the leading cause of mortality among the cancer types. The receptor tyrosine kinase inhibitors (gefitinib, erlotinib, lapatinib) which have been applied in the therapy, are not able to inhibit the progression of this disease perfectly because of resistance. It has been demonstrated that the amplification of mesenchymal-epithelial transition factor (c-Met) or secondary mutation of EGFR kinase causes the resistance against EGFR inhibitors in 18-20 percent of the cases. Clinical candidates inhibiting both of EGFR and c-Met kinases are unknown in the literature. We have developed quinoline-based inhibitors in our research project, which inhibit both kinases in submicromolar range in enzymatic assays, moreover we have demonstrated by western blot analysis that these compounds inhibit the autophosphorylation in vivo. The binding of the effective compounds was examined by in silico and docking simulations.

Topics: Afatinib; Aminopyridines; Anilides; Antineoplastic Agents; Apoptosis; Blotting, Western; Carcinoma, Non-Small-Cell Lung; Cell Line; Cell Line, Tumor; Computer Simulation; Crizotinib; Drug Resistance, Neoplasm; ErbB Receptors; Erlotinib Hydrochloride; Gefitinib; Humans; Imidazoles; Lapatinib; Lung Neoplasms; Molecular Structure; Protein Kinase Inhibitors; Protein Kinases; Protein-Tyrosine Kinases; Proto-Oncogene Proteins c-met; Pyrazines; Pyrazoles; Pyridines; Pyridones; Quinazolines; Quinolines