Mechanisms of clinical resistance to small molecule tyrosine kinase inhibitors targeting oncogenic tyrosine kinases.
A number of highly specific small molecule inhibitors of oncogenic tyrosine kinases have been developed and may potentially improve the treatment of different malignant diseases. However, it became rapidly evident that multiple resistance mechanisms compromise the successful clinical application of these inhibitors, particularly in advanced solid tumors. To develop efficient therapeutic strategies with small molecule inhibitors, one must understand the causes for treatment failure. Three different types of resistance to small molecule inhibitors of oncogenic tyrosine kinases have been observed. The malignant phenotype may be independent of the activity of the target kinase (target-independent resistance). Alternatively, overexpression or mutation of the target kinase can counteract the inhibition of oncogenic tyrosine kinases (target-dependent resistance). Finally, alterations of drug transporters or drug-metabolizing pathways may block the bioavailability of the tyrosine kinase inhibitors (drug-dependent resistance). This article reviews the current knowledge of clinical resistance to small molecule inhibitors approved for treatment of cancer patients.
van der Kuip
Heiko
H
Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.
Wohlbold
Lara
L
Oetzel
Carsten
C
Schwab
Matthias
M
Aulitzky
Walter E
WE
D000818:Animals; D001549:Benzamides; D019008:Drug Resistance, Neoplasm; D006801:Humans; D000068877:Imatinib Mesylate; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D010879:Piperazines / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D011743:Pyrimidines / Q000627:therapeutic use
D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases