János Bolyai Research Scholarship of the Hungarian Academy of Sciences
(ÚNKP-20-5-SE-1)
(UNKP-20-3-II-SE-8)
(NTP-NFTÖ-20-B-0314)
Baseline or acquired resistance to docetaxel (DOC) represents a significant risk for
patients with metastatic prostate cancer (PC). In the last years, novel therapy regimens
have been approved providing reasonable alternatives for DOC-resistant patients making
prediction of DOC resistance of great clinical importance. We aimed to identify serum
biomarkers, which are able to select patients who will not benefit from DOC treatment.
DOC-resistant PC3-DR and DU145-DR sublines and their sensitive parental cell lines
(DU145, PC3) were comparatively analyzed using liquid chromatography-coupled tandem
mass spectrometry (LC-MS/MS). Results were filtered using bioinformatics approaches
to identify promising serum biomarkers. Serum levels of five proteins were determined
in serum samples of 66 DOC-treated metastatic castration-resistant PC patients (mCRPC)
using ELISA. Results were correlated with clinicopathological and survival data. CD44
was subjected to further functional cell culture analyses. We found at least 177 two-fold
significantly overexpressed proteins in DOC-resistant cell lines. Our bioinformatics
method suggested 11/177 proteins to be secreted into the serum. We determined serum
levels of five (CD44, MET, GSN, IL13RA2 and LNPEP) proteins in serum samples of DOC-treated
patients and found high CD44 serum levels to be independently associated with poor
overall survival (p = 0.001). In accordance, silencing of CD44 in DU145-DR cells resulted
in re-sensitization to DOC. In conclusion, high serum CD44 levels may help identify
DOC-resistant patients and may thereby help optimize clinical decision-making regarding
type and timing of therapy for mCRPC patients. In addition, our in vitro results imply
the possible functional involvement of CD44 in DOC resistance.
