Inhibitor of differentiation-1 as a novel prognostic factor in NSCLC patients with adenocarcinoma histology and its potential contribution to therapy resistance

PURPOSE
High inhibitor of differentiation-1 (Id1) levels have been found in some tumor types. We aimed to study Id1 levels and their prognostic impact in a large series of stage I-IV non-small-cell lung cancer (NSCLC) patients. Experiments in cell lines and cells derived from malignant pleural effusions (MPEs) were also performed.

EXPERIMENTAL DESIGN
A total of 346 NSCLC samples (three different cohorts), including 65 matched non-malignant tissues, were evaluated for Id1 expression using immunohistochemistry. Additional data from a fourth cohort including 111 patients were obtained for Id1 mRNA expression analysis using publicly available microarrays. In vitro proliferation assays were performed to characterize the impact of Id1 on growth and treatment sensitivity.

RESULTS
Significantly higher Id1 protein levels were found in tumors compared to normal tissues (p<0.001) and in squamous carcinomas compared to adenocarcinomas (p<0.001). In radically treated stage I-III patients and stage IV patients treated with chemotherapy, higher Id1 levels were associated with a shorter disease-free survival (DFS) and overall survival (OS) in adenocarcinoma patients in a log rank test. A Cox model confirmed the indepent prognostic value of Id1 levels for both stage I-III and stage IV patients. In silico analysis confirmed a correlation between higher Id1 mRNA levels and poor prognosis for adenocarcinoma subjects. In vitro Id1 silencing in radio/chemotherapy-resistant adenocarcinoma cells from MPEs restored sensitivity to both therapies.

CONCLUSIONS
In our series, Id1 levels showed an independent prognostic value in patients with adenocarcinoma, regardless of the stage. Id1 silencing may sensitize adenocarcinoma cells to radiotherapy and chemotherapy.

CITATION  Clin Cancer Res. 2011 Jun 15;17(12):4155-66.
doi: 10.1158/1078-0432.CCR-10-3381. Epub 2011 May 3.