L1 cell adhesion molecule (L1CAM) expression in endometrial cancer is associated with SRC pathway activation with potential for targeted therapy with dasatinib

Abstract

<h3>Objectives:</h3> L1 cell adhesion molecule (L1CAM) immunohistochemical (IHC) staining has been shown as a prognostic marker of poor outcome in endometrial cancer. This study investigates the protein expression and transcriptome profiles of this prognostic marker in endometrial cancer and how L1CAM expression can subsequently be used for risk stratification and targeted therapy. <h3>Methods:</h3> Primary tumor specimens were obtained from a consecutive cohort of 159 women with newly diagnosed endometrial cancer of any stage, 131 were stained for L1CAM expression. mRNA transcriptome analysis was performed on 110 fresh frozen tumor specimens using Agilent gene expression arrays. L1CAM staining and transcriptome profiles were analyzed. Pathway analysis using PARADIGM was performed. IC50 analysis for Dasatinib was undertaken for known in vitro L1CAM positive endometrial cancer cell lines. <h3>Results:</h3> L1CAM staining was positive in 26 of 131 tumors tested (19.9%). L1CAM positivity, compared with L1CAM negativity, was significantly associated with younger age at primary surgery (59.8±11.5 vs. 66.0±13.9, p=0.04), histologic subtypes other than endometrioid (50.0% vs 6.7%, p<0.0001), grade 2-3 (61.6 vs 56.2%, p<0.0001), advanced stage disease (42.0% vs 22.1%, p=0.002), LVSI (42.3% vs 21.9%, p=0.05), distant metastasis (19.2% vs 7.6%, p=0.02), and high risk by GOG 99 criteria (65.4% vs 29.5%, p=0.003) Transcriptome analysis identified 197 genes significantly upregulated in L1CAM positive vs negative tumors. Three biologic pathways with potential clinical relevance were found to be statistically enriched within this gene set: 1) KRAS pathway activation, 2) SRC pathway activation, and 3) <i>BRCA1</i> loss of function. The SRC/Abl kinase inhibitor, dasatinib, demonstrated anti-proliferative effect in endometrial cancer cell lines over expressing L1CAM, suggesting that this may be a promising targetable pathway in these molecular high risk patients. <h3>Conclusions:</h3> L1CAM positive molecular high risk endometrial cancers might be driven by the src pathway. Dasatinib, a small molecule src inhibitor, may be one possible therapeutic option for those patients, warranting further research.