期刊
SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY
卷 50, 期 -, 页码 164-176出版社
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.semcdb.2015.09.018
关键词
Feedback regulation; Gatekeeper mutation; Network biology; Protein kinase; Resistance to drugs; Signal transduction
资金
- European Research Council
- Israel Cancer Research Fund
- Israel Science Foundation
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
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. (C) 2015 Elsevier Ltd. All rights reserved.
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