Pharmacodynamic studies of the epidermal growth factor receptor inhibitor ZD1839 in skin from cancer patients: histopathologic and molecular consequences of receptor inhibition.
OBJECTIVE
The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor ZD1839 (Iressa; AstraZeneca Pharmaceuticals, Alderley Park, United Kingdom) is under development as an anticancer agent. We studied the pharmacodynamic effects of ZD1839 on EGFR in the skin, an EGFR-dependent tissue, in cancer patients participating in ZD1839 phase I clinical trials.


METHODS
We studied 104 pre- and/or on-ZD1839 therapy ( approximately at day 28 of therapy) skin biopsies from 65 patients receiving escalating doses of daily oral ZD1839. We measured ZD1839 effects on EGFR activation by immunohistochemistry using an antibody specific for the activated (phosphorylated) EGFR. Effects on receptor signaling (activated mitogen-activated protein kinase [MAPK]), proliferation, p27(KIP1), and maturation were also assessed.


RESULTS
Histopathologically, the stratum corneum of the epidermis was thinner during therapy (P <.001). In hair follicles, prominent keratin plugs and microorganisms were found in dilated infundibula. ZD1839 suppressed EGFR phosphorylation in all EGFR-expressing cells (P <.001). In addition, ZD1839 inhibited MAPK activation (P <.001) and reduced keratinocyte proliferation index (P <.001). Concomitantly, ZD1839 increased the expression of p27(KIP1) (P <.001) and maturation markers (P <.001) and increased apoptosis (P <.001). These effects were observed at all dose levels, before reaching dose-limiting toxicities.


CONCLUSIONS
ZD1839 inhibits EGFR activation and affects downstream receptor-dependent processes in vivo. These effects were profound at doses well below the one producing unacceptable toxicity, a finding that strongly supports pharmacodynamic assessments to select optimal doses instead of a maximum-tolerated dose for definitive efficacy and safety trials.
Albanell
Joan
J
Oncology Service, Vall d'Hebron University Hospital, Paseo Vall d'Hebron 119-129, Barcelona 08035, Spain.
Rojo
Federico
F
Averbuch
Steve
S
Feyereislova
Andrea
A
Mascaro
Jose Manuel
JM
Herbst
Roy
R
LoRusso
Patricia
P
Rischin
Danny
D
Sauleda
Silvia
S
Gee
Julia
J
Nicholson
Robert I
RI
Baselga
Jose
J
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers; D018797:Cell Cycle Proteins / Q000187:drug effects; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D000077156:Gefitinib; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology*; D012867:Skin / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018709:Statistics, Nonparametric; D025521:Tumor Suppressor Proteins / Q000187:drug effects
D000970:Antineoplastic Agents; D015415:Biomarkers; D018797:Cell Cycle Proteins; D011799:Quinazolines; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D066246:ErbB Receptors; D000077156:Gefitinib