C-fos assessment as a marker of anti-epidermal growth factor receptor effect.
Factors predicting sensitivity to epidermal growth factor receptor (EGFR) blockade are largely unknown and new strategies are being sought to individualize cancer therapy. This study evaluated the variation in the expression of the early response gene c-fos as a distal effect of EGFR inhibition and its relationship to antitumor effects. The growth-inhibitory and c-fos-modulating effects of gefitinib and erlotinib in human cancer cell lines (A431, CAL27, HN11, HuCCT1, and Hep2) were determined. Next, these cell lines were xenografted in mice and treated for 14 days with gefitinib (A431 and HuCCT1) or erlotinib (CAL27, HN11, and Hep2). Fine needle aspiration biopsy of tumors was done at baseline and after 14 days of therapy for c-fos assessment. In addition, we tested the feasibility of analyzing this marker in five paired tumor samples from a clinical trial of gefitinib in patients with solid tumors. In culture, gefitinib and erlotinib decreased c-fos mRNA levels in the susceptible cell lines A431, CAL27, and HN11; however, both drugs failed to achieve c-fos inhibition in resistant cells. Gefitinib or erlotinib abrogated the increase in c-fos expression in vivo in EGFR-sensitive A431, CAL27, and HN11 tumors but not in resistant strains. Ex vivo evaluation was feasible and predicted in vivo effects. The feasibility study in paired human tumor biopsies showed that this biomarker can be reliably measured in clinical materials. In summary, variations in c-fos expression reflect the pharmacologic actions of EGFR inhibitors in in vitro and in vivo models.
The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231-1000, USA.
Antonio
A
Jimeno
Peter
P
Kulesza
Erik
E
Kincaid
Nadia
N
Bouaroud
Audrey
A
Chan
Arlene
A
Forastiere
Julie
J
Brahmer
Douglas P
DP
Clark
Manuel
M
Hidalgo
D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000096:biosynthesis / Q000235:genetics; D048708:Cell Growth Processes / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D000069347:Erlotinib Hydrochloride; D005260:Female; D000077156:Gefitinib; D016762:Genes, fos / Q000187:drug effects*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis / Q000235:genetics*; D011799:Quinazolines / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis* / Q000096:biosynthesis / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
D014408:Biomarkers, Tumor; D047428:Protein Kinase Inhibitors; D016760:Proto-Oncogene Proteins c-fos; D011799:Quinazolines; D012333:RNA, Messenger; D004815:Epidermal Growth Factor; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D000077156:Gefitinib