Inhibiting tyrosine kinases: successes and limitations.
Seminal studies with STI-571 and Herceptin in chronic myeloid leukemia, gastrointestinal stromal tumors, and breast cancer have clearly demonstrated that blockade of pathogenic tyrosine kinases can alter the natural history of appropriately selected human tumors. On the other hand, trials with EGF receptor inhibitors in unselected populations have shown anywhere from modest to no clinical activity. I will contrast below aspects in the development of inhibitors of Abl, c-Kit, HER2/neu (erbB2), and EGFR, highlight successes and pitfalls in this field, and propose some approaches for the future development of tyrosine kinase inhibitors in human cancer.
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001549:Benzamides; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology; D002986:Clinical Trials as Topic; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D006801:Humans; D000068877:Imatinib Mesylate; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D010879:Piperazines / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000627:therapeutic use; D000068878:Trastuzumab
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D000068878:Trastuzumab