Identification of p27/KIP1 expression level as a candidate biomarker of response to rapalogs therapy in human cancer.
Rapamycin analogs temsirolimus and everolimus have been approved for the treatment of advanced renal cancer and are being tested in a wide spectrum of human tumors. However, objective response rates with rapalogs in clinical trials were modest and variable. Identification of biomarkers capable of predicting response to rapalogs is of increasing interest. We analyzed pairwise Pearson correlation coefficients (r) between rapalogs activity and gene expression profile for each NCI-60 cell line. p27 showed the highest positive correlation among 9,706 gene probes tested. At cellular levels, breast cancer MCF-7, T47D, and BT-474 cells, expressing high levels of p27, were sensitive to rapalogs, whereas the cells expressed low levels of p27, such as MDA-MB-231, MDA-MB-468, and MDA-MB-435 cells, exhibited resistance to rapalogs. Mechanistic study indicated that this correlation is likely determined by the basal level of p27 regardless of the phosphorylation or redistribution of p27 upon rapalogs treatment, which may provide a putative threshold to block G1/S transition. Consistently, down-regulation of p27 by siRNA conferred MCF-7 and BT-474 cells insensitive to rapalogs. Moreover, a significant positive correlation between p27 gene expression and rapamycin anti-tumor activity was also observed in mice bearing different human cancer cell xenografts. In conclusion, p27 expression level is positively correlated with the anticancer activity of rapalogs in vitro and in vivo. We propose p27 expression level may be also a candidate predictive biomarker for patient selection for rapalogs-based therapy, which requires clinical validation in a series of patients treated with rapalogs.
Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Zhang Jiang Hi-Tech Park, Pudong, Shanghai 201203, China.
Guang
G
Chen
Na
N
Yang
Xiang
X
Wang
Si-Yuan
SY
Zheng
Yi
Y
Chen
Lin-Jiang
LJ
Tong
Yi-Xue
YX
Li
Ling-Hua
LH
Meng
Jian
J
Ding
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014183:Transplantation, Heterologous
D015415:Biomarkers; D047428:Protein Kinase Inhibitors; D050760:Cyclin-Dependent Kinase Inhibitor p27; C401859:temsirolimus; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus