Inhibiting Wnt/beta‐catenin in CTNNB1‐mutated endometrial cancer

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 CTNNB1mutant EC.

Inflammation-Related LncRNAs Signature for Prognosis and Immune Response Evaluation in Uterine Corpus Endometrial Carcinoma

“…Almost 40% of UCEC cases exhibit abnormal activation of the Wnt/β-catenin pathway. It has been shown that CT-NNB1 mutations leading to activation of the Wnt signaling pathway are bound up with high-grade UCEC in young women ( 51 ). As suggested by Chen et al., inhibition of MRP4 could block the viability and survival of endometrial tumors by targeting Wnt/β-catenin pathway ( 52 ).…”

Targeted Therapy for Adrenocortical Carcinoma: A Genomic-Based Search for Available and Emerging Options

“…Interestingly, it was more frequently altered in metastatic ACC, as opposed to localized stages ( Figure 2 ), suggesting that CTNNB1 could be involved in the switch to metastasis. On the targeting drug PRI-724, there are some data for HCC [ 42 ], breast cancer [ 43 ], colorectal cancer [ 44 ], endometrial cancer [ 45 ], sarcomas [ 46 ], and neuroendocrine tumors [ 47 ]. It has not been approved by the FDA yet and, to our best knowledge, has never been tested in ACC patients.…”

The Role of CTNNB1 in Endometrial Cancer

“…Hyperactivation of Wingless/int1 (Wnt)/ β -catenin signalling has been implicated in tumorigenesis, tumour progression, recurrence, and chemoresistance of gynaecological malignancies [ 11 , 18 – 20 ]. Specifically, Wnt signalling promotes metastasis and therapy resistance in ovarian cancer, plays a crucial role in tumorigenesis and recurrence in endometrial cancer, and participates in human papillomavirus (HPV) related tumorigenesis and metastasis in cervical cancer [ 21 ].…”

“…Tumours with mutations in CTNNB1 tend to have low-grade histology, low rates of myometrial invasion with low rates of LVSI. They usually occur in women with EC at younger age, which clinically indicates a low risk of recurrence [ 11 , 18 , 20 , 48 ]. However, mutations of CTNNB1 gene are related to worse outcomes with significantly increased rate of disease recurrence and lower overall survival, compared to other tumours with low-grade histology, specifically in relation to mutations in exon 3 [ 20 , 52 ].…”

“…They usually occur in women with EC at younger age, which clinically indicates a low risk of recurrence [ 11 , 18 , 20 , 48 ]. However, mutations of CTNNB1 gene are related to worse outcomes with significantly increased rate of disease recurrence and lower overall survival, compared to other tumours with low-grade histology, specifically in relation to mutations in exon 3 [ 20 , 52 ]. This shows the necessity of integrating molecular markers to adequately assess the prognosis of tumours with low-grade histopathological characteristics to adjust therapeutical solutions and offer possibility of targeted therapy.…”