Tumor transcriptome reveals the predictive and prognostic impact of lysosomal protease inhibitors in non-small-cell lung cancer

Russell David Petty, Keith Kerr, Graeme Ian Murray, Marianne Nicolson, P. H. Rooney, Donald Bissett, Elaina Susan Renata Collie-Duguid

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

PURPOSE: Insight into clinical response to platinum-based chemotherapy (PBC) in non-small-cell lung cancer (NSCLC).

METHODS: Matched tumor and nontumor lung tissues from PBC-treated NSCLC patients (four nonresponders and four responders) and tumor tissue from an independent test set (four nonresponders and four responders), were profiled using microarrays. Lysosomal protease inhibitors SerpinB3 and cystatin C were highly correlated with clinical response and were further evaluated by immunohistochemistry in PBC-treated patients (36 prechemotherapy and 13 postchemotherapy). Investigation of the pathogenic and prognostic significance of SerpinB3 was performed in 251 primary tumors, with 64 regional lymph node pairs, from chemotherapy-naïve NSCLC patients using immunohistochemistry.

RESULTS: Bioinformatic analyses of gene expression in the training set identified a gene set (n = 17) that separated all patients in the training and test sets (n = 16) according to response in hierarchical clustering. Transcriptome profiling revealed that SerpinB3 mRNA was highly correlated with degree of response (r = -0.978; P < .0001) and was a clear outlier (nonresponders:responders > 50-fold). SerpinB3 protein expression was correlated with clinical response in PBC-treated NSCLC patients (P = .045). Expression of SerpinB3 and cystatin C, relative to the target, protease cathepsin B, was independently predictive of response (odds ratio, 17.8; 95% CI, 2.0 to 162.4; P = .01), with an accuracy of 72%. High SerpinB3 expression levels, invariably associated with chemoresistance, had contrasting prognostic impact in untreated squamous cell carcinomas (hazard ratio [HR], 0.43; 95% CI, 0.18 to 0.93) or adenocarcinomas (HR, 2.09; 95% CI, 1.03 to 4.72).

CONCLUSION: This provides the first comprehensive molecular characterization of clinical responsiveness to PBC in NSCLC and reveals the predictive and prognostic impact of two lysosomal protease inhibitors, potentially representing novel targets for NSCLC therapeutics.

Original languageEnglish
Pages (from-to)1729-1744
Number of pages16
JournalJournal of Clinical Oncology
Volume24
Issue number11
DOIs
Publication statusPublished - 10 Apr 2006

Keywords

  • gene expression profiles
  • carcinoma antigen
  • cathepsin B
  • anticancer drugs
  • messenger RNA
  • chemosensitivity
  • survival
  • therapy
  • death
  • adenocarcinoma

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