Tyrosine kinase inhibitors: why does the current process of clinical development not apply to them?
The robust clinical activity of imatinib and trastuzumab for treatment of chronic myeloid leukemia, gastrointestinal stromal tumors, and breast cancer has demonstrated that blocking pathogenic tyrosine kinases can alter the natural history of human tumors. On the other hand, EGF receptor inhibitors have shown overall modest activity. The contrast in the development of these agents implies that both molecular target dependence and patient selection are essential for the successful outcome of this process. We will contrast lessons derived from the development of inhibitors of Abl, c-Kit, HER2/neu (erbB2), and EGFR, highlight successes and limitations in the field, and propose new approaches for clinical development of tyrosine kinase inhibitor therapy.
Arteaga
Carlos L
CL
Department of Medicine, Vanderbilt-Ingram Comprehensive Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA. carlos.arteaga@vanderbilt.edu
Baselga
Jose
J
D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D001549:Benzamides; D045744:Cell Line, Tumor; D002986:Clinical Trials as Topic; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D009154:Mutation; D016374:Oncogene Proteins v-abl / Q000378:metabolism; D010879:Piperazines / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D011743:Pyrimidines / Q000627:therapeutic use; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D000068878:Trastuzumab
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D001549:Benzamides; D004791:Enzyme Inhibitors; D066246:ErbB Receptors; D000068877:Imatinib Mesylate; D016374:Oncogene Proteins v-abl; D010879:Piperazines; D011505:Protein-Tyrosine Kinases; D019009:Proto-Oncogene Proteins c-kit; D011743:Pyrimidines; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab