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.
Blagosklonny
Mikhail V
MV
Brander Cancer Research Institute, New York Medical College, Hawthorne, New York 10532 USA. M_Blagosklonny@NYMC.EDU
Darzynkiewicz
Zbigniew
Z
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