zd-6474 and Carcinoma--Non-Small-Cell-Lung

The pyrimidine core-containing compound Osimertinib is the only epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) from the third generation that has been approved by the U.S. Food and Drug Administration to target threonine 790 methionine (T790M) resistance while sparing the wild-type epidermal growth factor receptor (WT EGFR). It is nearly 200-fold more selective toward the mutant EGFR as compared to the WT EGFR. A tertiary cystein 797 to serine 797 (C797S) mutation in the EGFR kinase domain has hampered Osimertinib treatment in patients with advanced EGFR-mutated non-small-cell lung cancer (NSCLC). This C797S mutation is presumed to induce a tertiary-acquired resistance to all current reversible and irreversible EGFR TKIs. This review summarizes the molecular mechanisms of resistance to Osimertinib as well as different strategies for overcoming the EGFR-dependent and EGFR-independent mechanisms of resistance, new challenges, and a future direction.

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

A new chimeric fusion transcript of KIF5B (the kinesin family 5B gene) and the RET (Rearranged during Transcription) oncogene, KIF5B-RET, was found in 1-2% of lung adenocarcinomas (LADCs) in late 2011. Several related clinical trials for non-small-cell lung cancer (NSCLC) with KIF5B-RET rearrangements using existing RET inhibitors, such as lenvatinib, vandetanib, sunitinib, ponatinib, cabozantinib, and AUY922, have been swiftly initiated by the discovery of the KIF5B-RET fusion gene. Anti-RET activity and the status of clinical development of these known RET tyrosine kinase inhibitors (TKIs) for KIF5B-RET fusion-positive NSCLC are discussed. A kinase inhibitor that can target a driver mutation specifically may lead to a superior clinical benefit compared with broad-spectrum kinase inhibitors. In this regard, an analysis of the structure of RET kinase and its complex with known RET inhibitors are also briefly discussed.

Topics: Animals; Antibodies, Monoclonal; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Humans; Kinesins; Lung Neoplasms; Models, Molecular; Protein Conformation