title: Mutational and network level mechanisms underlying resistance to anti-cancer kinase inhibitors.
abstract: Tyrosine-specific and other protein kinases are embedded in signaling networks critical for progression of tumors of all types. Hence, kinase inhibitors have nucleated a major arm of personalized cancer therapy. Unfortunately, almost all kinase inhibitors evoke resistance within a year or two, due to secondary mutations, and other alterations within the targeted kinase, or due to emergence of feedback regulatory loops that compensate for extinguished kinases. We review clinically approved kinase inhibitors and the emergence of resistance in leukemia, melanoma, lung and breast tumors, and draw parallel lines in terms of secondary mutations and compensatory mechanisms. Currently emerging are pharmacological strategies able to circumvent resistance and re-sensitize patients to therapeutic treatments. They include second and third generation inhibitors that overcome new mutations, novel drug combinations that simultaneously block the primary oncogenic pathway and compensatory routes, as well as monoclonal antibodies. Deeper understanding of biological signaling networks and their responses to perturbations will aid in the development of effective therapies for patients with cancer.
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Maicol
authors.initials: M
authors.lastname: Mancini
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel. Electronic address: Yosef.Yarden@weizmann.ac.il.
authors.forename: Yosef
authors.initials: Y
authors.lastname: Yarden
mesh_terms: D000818:Animals; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D025461:Feedback, Physiological / Q000187:drug effects; D006801:Humans; D009154:Mutation / Q000235:genetics*; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D047428:Protein Kinase Inhibitors
keywords: Feedback regulation; Gatekeeper mutation; Network biology; Protein kinase; Resistance to drugs; Signal transduction