Identification of p27/KIP1 expression level as a candidate biomarker of response to rapalogs therapy in human cancer

Guang Chen, Na Yang, Xiang Wang, Siyuan Zheng, Yi Chen, Lin Jiang Tong, Yi Xue Li, Ling Hua Meng, Jian Ding

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)941-952
Number of pages12
JournalJournal of Molecular Medicine
Volume88
Issue number9
DOIs
StatePublished - Sep 1 2010
Externally publishedYes

Fingerprint

Biomarkers
Sirolimus
Neoplasms
Therapeutics
Kidney Neoplasms
Transcriptome
Heterografts
Patient Selection
Small Interfering RNA
Down-Regulation
Phosphorylation
Clinical Trials
Breast Neoplasms
Gene Expression
Cell Line
Genes

Keywords

  • Biomarker
  • Cancer
  • mTOR
  • p27
  • Rapalogs
  • Rapamycin

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery
  • Genetics(clinical)

Cite this

Identification of p27/KIP1 expression level as a candidate biomarker of response to rapalogs therapy in human cancer. / Chen, Guang; Yang, Na; Wang, Xiang; Zheng, Siyuan; Chen, Yi; Tong, Lin Jiang; Li, Yi Xue; Meng, Ling Hua; Ding, Jian.

In: Journal of Molecular Medicine, Vol. 88, No. 9, 01.09.2010, p. 941-952.

Research output: Contribution to journalArticle

Chen, Guang ; Yang, Na ; Wang, Xiang ; Zheng, Siyuan ; Chen, Yi ; Tong, Lin Jiang ; Li, Yi Xue ; Meng, Ling Hua ; Ding, Jian. / Identification of p27/KIP1 expression level as a candidate biomarker of response to rapalogs therapy in human cancer. In: Journal of Molecular Medicine. 2010 ; Vol. 88, No. 9. pp. 941-952.
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