Effects of EGFR tyrosine kinase inhibitor erlotinib in prostate cancer cells in vitro.
BACKGROUND
Erlotinib is a small-molecule tyrosine kinase inhibitor targeted EGFR, known to be overexpressed in a variety of cancers, including prostate cancer. Clinical trials showed insignificant clinical benefit in patients with castration resistant prostate cancer both when EGFR inhibitors were administered as monotherapy or in association with antiandrogens or chemotherapeutics. Why, differently to other tumors, have EGFR inhibitors been so ineffective in human prostate cancer? This is the question that we have set in this report.


METHODS
For this purpose, the effectiveness of erlotinib, a selective EGFR inhibitor, in a wide range of prostate cancer cells (wild type or engineered to overexpress peculiar proteins including androgen receptor and PTEN).


RESULTS
We demonstrated that the effectiveness of erlotinib was inversely correlated to the EGFR/Her2 ratio rather than EGFR/p-EGFR or Her2/p-Her2 levels. Chronic treatment with bicalutamide induced overexpression of Her2 and reduction of EGFR/Her2ratio and this was associated with increased Akt and Erk activity. In these conditions of treatment a reduced efficacy of erlotinib was observed. At the same time, an increased efficacy versus erlotinib was documented in cancer cells chronically exposed to DHT. In these culture conditions low levels of Her2 and increased EGFR/Her2 ratio were evidenced.


CONCLUSIONS
Taken together, our results seem to suggest that a low EGFR/Her2 ratio and PTEN absence are the main factors responsible of erlotinib inefficacy. Therefore the inhibition of EGFR could have important antitumor effects in hormone-naive rather than in hormonally treated patients.
Festuccia
Claudio
C
Laboratory of Radiobiology, Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy. claudio.festuccia@univaq.it
Gravina
Giovanni Luca
GL
Biordi
Leda
L
D'Ascenzo
Sandra
S
Dolo
Vincenza
V
Ficorella
Corrado
C
Ricevuto
Enrico
E
Tombolini
Vincenzo
V
D017209:Apoptosis / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D034741:RNA, Small Interfering; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D018797:Cell Cycle Proteins; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human