Identification of candidate biomarkers of therapeutic response to docetaxel by proteomic profiling
Docetaxel chemotherapy improves symptoms and survival in men with metastatic hormone-refractory prostate cancer (HRPC). However, about 50% of patients do not respond to Docetaxel but are exposed to significant toxicity without direct benefit. This study aimed to identify novel therapeutic targets and predictive biomarkers of Docetaxel-resistance in HRPC. We used iTRAQ-mass spectrometry analysis to identify key proteins involved in the development of Docetaxel resistance using Docetaxel sensitive PC3 cells and Docetaxel-resistant PC3 cell line (PC3-Rx) developed by Docetaxel dose-escalation. Functional validation experiments were performed using recombinant protein treatment and siRNA knockdown experiments. Serum/plasma levels of the targets in patient samples were measured by ELISA. The IC50 for Docetaxel in the PC3-Rx cells was 13-fold greater than the parent PC-3 cell line (p=0.004). Protein profiling identified MIC-1 and AGR2 as respectively up- and down regulated in Docetaxel resistant cells. PC-3 cells treated with recombinant MIC-1 also became resistant to Docetaxel (p=0.03). Conversely, treating PC3-Rx cells with MIC1- siRNA restored sensitivity to Docetaxel (p=0.02). Knockdown of AGR2 expression in PC3 cells resulted in Docetaxel resistance (p=0.007). Furthermore, increased serum/plasma levels of MIC-1 after cycle one of chemotherapy was associated with progression of the cancer (p=0.006) and shorter survival after treatment (p=0.002). Overall, these results suggest that both AGR2 and MIC-1 play a role in Docetaxel resistance in HRPC. In addition, a rise in serum/plasma MIC-1 level after cycle one of Docetaxel may be an indication to abandon further treatment. Further investigation of MIC-1 as a biomarker and therapeutic target for Docetaxel-resistance HRPC is clearly warranted.
|Authors||Zhao, L.; Lee, B.Y.; Brown, D.A.; Molloy, M.P.; Marx, G.M.; Pavlakis, N.; Boyer, M.J.; Stockler, M.; Kaplan, W.; Breit, S.N.; Sutherland, R.L.; Henshall, S.M.; Horvath, L.G.|
|Publisher Name||CANCER RESEARCH|
|Published Date||2009-10-01 00:00:00|
|URL link to publisher's version||http://www.ncbi.nlm.nih.gov/pubmed/19773444|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/10076|