Why Iressa failed: toward novel use of kinase inhibitors (outlook).
A phase III failure of Iressa, an inhibitor of the EGF receptor (EGFR), is viewed as a surprise. With a few exceptions, however, inhibitors of EGFR cannot be effective as a monotherapy in cancers with additional oncogenic changes (downstream of EGFR), which cause mitogen-independent proliferation. In other cases, combining these inhibitors with chemotherapy may lead to antagonism in cancer cells and/or aggravated side-effects. This review discusses why neither levels of EGFR nor doses of Iressa correlate with clinical response. We suggest a novel use of signal transduction inhibitors, including Iressa, to increase therapeutic index by modulating cycle-dependent and apoptosis-inducing chemotherapies. This approach may be most beneficial to patients who do not respond to monotherapy with kinase inhibitors. Development of molecular diagnostics will further diversify these strategies.
Brander Cancer Research Institute, New York Medical College, Hawthorne, New York 10532 USA. M_Blagosklonny@NYMC.EDU
Mikhail V
MV
Blagosklonny
Zbigniew
Z
Darzynkiewicz
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017326:Clinical Trials, Phase III as Topic; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors*; D066246:ErbB Receptors / Q000378:metabolism; D000077156:Gefitinib; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011799:Quinazolines / Q000627:therapeutic use*; D017211:Treatment Failure
D000970:Antineoplastic Agents; D011799:Quinazolines; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D000077156:Gefitinib