In an article published on September, 2017, in Molecular Cancer Therapeutics, Zeng and colleagues showed that the WNT/β-catenin oncogenic pathway was activated in a subset of human gastrointestinal stromal tumors (GIST) and that inhibiting its signaling alone or in combination with imatinib has antitumor efficacy in vitro and in vivo in imatinib-sensitive and resistant preclinical models. However, they concluded that “more investigation is needed to correlate β-catenin activation with clinicopathologic features in GIST clinical samples.” Here, we examined the activation score of the β-catenin pathway in 160 clinically annotated clinical samples of operated primary GISTs. We showed that the β-catenin activation score, assessed as continuous variable, was heterogeneous across samples. Higher score was associated with certain prognostic clinicopathologic characteristics, including mutational status, tumor size, and AFIP classification, and even more importantly, with more postoperative relapses in uni- and multivariate analyses. Such unfavorable independent prognostic value of β-catenin activation reinforces the potential therapeutic value of this new target in GIST and nicely complements Zeng's study. Mol Cancer Ther; 17(1); 327–8. ©2018 AACR.

In the September issue of Molecular Cancer Therapeutics (1), Zeng and colleagues show that the WNT/β-catenin signaling represents “a novel therapeutic target for selected gastrointestinal stroma tumors (GISTs).” GISTs, the most frequent digestive sarcomas, are an exemplary model for molecular-based treatment in oncology because of the presence of activating KIT or PDGFRA mutations in approximately 85% of cases and the resulting high sensitivity to tyrosine kinase inhibitors, notably first-line imatinib. However, despite imatinib effectiveness, it is crucial to develop therapies able to overcome the molecular mechanisms of resistance to imatinib (2). In this context, Zeng's study represents a promising new avenue of research. The authors show that the WNT/β-catenin oncogenic pathway is activated in a subset of human GISTs and that inhibiting its signaling alone or in combination with imatinib has antitumor efficacy in vitro and in vivo in imatinib-sensitive and resistant preclinical models. The authors conclude that “more investigation is needed to correlate β-catenin activation with clinicopathological features in GIST clinical samples.”

To address this issue, we analyzed the gene expression profiles of 160 clinically annotated samples of operated primary GISTs (3). Profiles had been generated using DNA microarrays and gathered from six public datasets. For each sample, we measured the activation score of the β-catenin pathway based on a transcriptional signature (4). This activation score, assessed as a continuous variable, was heterogeneous across all samples (Supplementary Fig. S1A), allowing to search for clinicopathologic correlations. Higher score was associated with mutational status (higher in KIT exon 11 mutation; P = 2.30E−02), tumor size (higher in larger tumors; P = 1.81E−04), and AFIP classification (higher in high-risk; P = 2.75E−06). Positive correlation existed with mRNA expression of CDC25A and CUL4A, two known WNT target genes, as reported in sarcomas (5). After surgery, no patient had received adjuvant imatinib, and 32 relapsed during follow-up. In univariate prognostic analysis, high β-catenin activation score (OR = 194; 95% CI, 39.19–960; P = 6.01E−08; Supplementary Fig. S1B), KIT exon 9 mutation (P = 3.32E−02), large tumor size (P = 2.90E−03), and AFIP high-risk (P = 5.90E−16) were associated with more relapses (logistic regression). In multivariate analysis, the β-catenin activation score remained significant (P = 3.00E−02), suggesting independent prognostic value. High and low activation scores were associated with respective 5-year disease-free survival of 54% [95% confidence interval (CI), 37–80] and 95% (95% CI, 89–100; P = 2.82E−05; Supplementary Fig. S1C).

The unfavorable prognostic role of β-catenin activation in a clinical series of samples reinforces the potential therapeutic value of this new target in GIST, thus nicely complementing Zeng's study.

No potential conflicts of interest were disclosed.

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