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Inhibiting Wnt/beta-catenin in CTNNB1-mutated endometrial cancer
Marisa R Moroney1, Elizabeth Woodruff2, Lubna Qamar2
1Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Aurora, Colorado, USA.
Abstract:
The role of β-catenin/TCF transcriptional activity in endometrial cancer (EC) recurrence is not well understood. We assessed the impact of Wnt/β-catenin inhibition in EC models. In an analysis of the Cancer Genome Atlas, we confirmed that CTNNB1 mutations are enriched in recurrent low-risk EC and showed that aberrant Wnt/β-catenin pathway activation is associated with recurrence. We studied CTNNB1-wildtype (HEC1B, Ishikawa) and CTNNB1-mutant (HEC108, HEC265, HEC1B-S33Y, Ishikawa-S33Y) EC cell lines. Dose response curves were determined for 5 Wnt/β-catenin pathway inhibitors (Wnt-C59, XAV-939, PyrPam, PRI-724, SM04690). XAV939, Wnt-C59 and PyrPam inhibited function upstream of β-catenin transcriptional activity and were ineffective at inhibiting cell viability. In contrast, PRI724 and SM04690 indirectly inhibited β-catenin transcriptional activity and significantly reduced cell viability in CTNNB1-mutant cell lines. Treatment with SM04690 reduced cell viability (Licor Cell stain) in all EC cell lines, but viability was significantly lower in CTNNB1-mutant cell lines (p < 0.01). Mechanistically, SM04690 significantly inhibited proliferation measured via 5'-bromo-2'-deoxyuridine incorporation and reduced T cell factor (TCF) transcriptional activity. HEC1B, HEC1B-S33Y and HEC265 tumor-bearing mice were treated with vehicle or SM04690. Tumors treated with SM04690 had smaller mean volumes than those treated with vehicle (p < 0.001, p = 0.014, p = 0.06). In HEC1B-S33Y and HEC265 tumors, SM04690 treatment significantly reduced Ki67 H-scores compared to vehicle (p = 0.035, p = 0.024). Targeting the Wnt/β-catenin pathway in CTNNB1-mutant EC effectively inhibited proliferation and β-catenin/TCF transcriptional activity and blunted tumor progression in in vivo models. These studies suggest β-catenin transcriptional inhibitors are effective in EC and particularly in CTNNB1-mutant EC, highlighting a potential therapeutic vulnerability for treatment of CTNNB1-mutant EC.
Insights
Targeting the Wnt/β-catenin pathway with inhibitors like SM04690 shows promise for treating endometrial cancer (EC). This approach effectively reduced tumor growth and proliferation, especially in CTNNB1-mutant EC, revealing a key therapeutic vulnerability.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Aberrant Wnt/β-catenin pathway activation is linked to endometrial cancer (EC) recurrence.
- CTNNB1 mutations are more prevalent in recurrent low-risk EC, suggesting a role in disease progression.
Purpose of the Study:
- To investigate the therapeutic potential of inhibiting the Wnt/β-catenin pathway in endometrial cancer models.
- To evaluate the efficacy of specific Wnt/β-catenin pathway inhibitors, particularly in CTNNB1-mutant EC cells.
Main Methods:
- Analysis of Cancer Genome Atlas data for CTNNB1 mutations in EC.
- In vitro drug screening of Wnt/β-catenin pathway inhibitors (Wnt-C59, XAV-939, PyrPam, PRI-724, SM04690) in EC cell lines.
- Assessment of cell viability, proliferation (5'-bromo-2'-deoxyuridine incorporation), and TCF transcriptional activity.
- In vivo studies using tumor-bearing mice treated with SM04690, measuring tumor volume and Ki67 expression.
Main Results:
- SM04690 and PRI724 significantly reduced cell viability in CTNNB1-mutant EC cell lines.
- SM04690 inhibited proliferation and TCF transcriptional activity in EC cells.
- SM04690 treatment led to smaller tumor volumes and reduced Ki67 expression in mouse models, particularly in CTNNB1-mutant tumors.
Conclusions:
- Targeting the Wnt/β-catenin pathway, especially with SM04690, effectively inhibits proliferation and tumor progression in endometrial cancer.
- CTNNB1-mutant EC presents a significant therapeutic vulnerability, suggesting that β-catenin transcriptional inhibitors could be a viable treatment strategy.
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