title: Strategies to overcome resistance to targeted protein kinase inhibitors.
abstract: Selective inhibition of protein tyrosine kinases is gaining importance as an effective therapeutic approach for the treatment of a wide range of human cancers. However, as extensively documented for the BCR-ABL oncogene in imatinib-treated leukaemia patients, clinical resistance caused by mutations in the targeted oncogene has been observed. Here, we look at how structural and mechanistic insights from imatinib-insensitive Bcr-Abl have been exploited to identify second-generation drugs that override acquired target resistance. These insights have created a rationale for the development of either multi-targeted protein kinase inhibitors or cocktails of selective antagonists as antitumour drugs that combine increased therapeutic potency with a reduced risk of the emergence of molecular resistance.
authors.affiliation: Axxima Pharmaceuticals AG, Max-Lebsche-Platz 32, 81377 München, Germany. henrik.daub@axxima.com
authors.forename: Henrik
authors.initials: H
authors.lastname: Daub
authors.forename: Katja
authors.initials: K
authors.lastname: Specht
authors.forename: Axel
authors.initials: A
authors.lastname: Ullrich
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry; D016503:Drug Delivery Systems / Q000379:methods*; D004351:Drug Resistance / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008969:Molecular Sequence Data; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors