Pharmacodynamic studies with the epidermal growth factor receptor tyrosine kinase inhibitor ZD1839.
ZD1839 is an orally active, selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that blocks signal transduction pathways implicated in the proliferation and survival of cancer cells, and other host-dependent processes promoting cancer growth. Based on its promising preclinical antitumor activity and favorable toxicity profile, ZD1839 has recently entered clinical trials. A particular challenge in the clinical development of this exciting compound is to explore its biological (pharmacodynamic) activity against the EGFR and receptor-dependent processes in serial biopsies. Such studies might be of assistance in predicting the subset of tumors that will benefit from therapy. They also may prove whether complete EGFR blockade is achieved in vivo. This latest point is particularly relevant because an optimal biological dose (ie, a dose resulting in complete receptor inhibition) would be preferred to the maximally tolerated dose that is being used with conventional nontargeted chemotherapeutic drugs. A series of preclinical studies have identified potentially useful surrogate markers of EGFR activity (eg, phosphorylation of EGFR and downstream receptor-dependent molecules such as mitogen-activated protein kinase [MAPK], Akt, or p27) that could be used as a surrogate marker of ZD1839 efficacy. In various tumor types, such as head and neck squamous carcinoma and gastric and breast adenocarcinoma, a relationship between EGFR and downstream markers (such as phosphorylated MAPK) has been characterized, further supporting the potential of these molecules for pharmacodynamic studies. Preliminary analysis of serial skin biopsies from patients participating in phase I trials has shown that ZD1839 results in substantial changes in EGFR-dependent molecules, such as phosphorylated MAPK, p27, phosphorylated STAT3, and others. Based on these encouraging results, studies assessing activated EGFR, activated MAPK, and other selected markers in phase II trials in tumors from patients treated with ZD1839 are currently planned or ongoing.
Albanell
J
J
Medical Oncology Service, Vall d'Hebron Hospital, Barcelona, Spain.
Rojo
F
F
Baselga
J
J
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002986:Clinical Trials as Topic; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D000077156:Gefitinib; D006801:Humans; D008024:Ligands; D020928:Mitogen-Activated Protein Kinases; D011799:Quinazolines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D008024:Ligands; D011799:Quinazolines; D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases; D000077156:Gefitinib