Targeting Wnt/Beta-Catenin Signaling in HPV-Positive Head and Neck Squamous Cell Carcinoma

Abstract

Wnt/Beta-Catenin signaling is involved in the carcinogenesis of different solid malignant tumors. The interaction of Creb-binding protein (CBP) with Beta-Catenin is a pivotal component of the Wnt/Beta-Catenin signaling pathway. The first aim of this study was to evaluate the association of CBP expression with survival in patients with human papillomavirus (HPV)-positive head and neck squamous cell carcinoma (HNSCC). Second, the in vitro effects of the inhibition of CBP/Beta-Catenin interaction were analyzed. In particular, the effects of ICG-001, an inhibitor of CBP/Beta-Catenin interaction, on proliferation, cell death, modulation of Wnt/Beta-Catenin target expression, and cell migration were examined in vitro. High CBP expression is significantly associated with better survival on mRNA and protein levels. Furthermore, we observed cytotoxic as well as anti-migratory effects of ICG-001. These effects were particularly more potent in the HPV-positive than in the -negative cell line. Mechanistically, ICG-001 treatment induced apoptosis and led to a downregulation of CBP, c-MYC, and Cyclin D1 in HPV-positive cells, indicating inhibition of Wnt/Beta-Catenin signaling. In conclusion, high CBP expression is observed in HPV-positive HNSCC patients with a good prognosis, and ICG-001 showed a promising antineoplastic potential, particularly in HPV-positive HNSCC cells. Therefore, ICG-001 may potentially become an essential component of treatment de-escalation regimens for HPV-positive HNSCC. Further studies are warranted for additional assessment of the mechanistic background of our in vitro findings.

Inhibition of beta-catenin shows therapeutic potential in head and neck squamous cell carcinoma in vitro

“…Synergistic effects were observable at 2 Gy which is also favorable from a clinical standpoint, since sessions with doses of 2 Gy are used in the primary care of HNSCC tumors [ 30 ]. These results are in line with other studies, that showed increased cytotoxicity of irradiation in combination with a targeted drug in HNSCC cells [ 24 , 31 ].…”

“…As noted, no viable results could be obtained for the SCC154 cells, since these cells need cell–cell contact to proliferate. Similarly, in lung adenocarcinoma, breast cancer, colorectal cancer, and HNSCC a reduced migratory potential upon Wnt pathway inhibition has been observed in the past [ 24 , 25 , 32 – 34 ]. In addition, probing for cleaved Caspase 3/7 upon MSAB revealed induction of apoptosis in treated HNSCC cells.…”

“…The diagnostic and prognostic potential of the WBC pathway in HNSCC is well-established and was shown specifically for HPV-positive disease previously by our group [ 24 ]. Indeed, we observed better prognosis in patients with a high expression of a WBC-specific protein.…”

“…Regarding inhibitors of the WBC pathway, ICG-001 has already been studied for its antineoplastic effects in HPV-negative and HPV-positive cell lines [ 24 ]. It showed anti-proliferative and anti-migratory as well as induction of apoptosis and reduction of WBC pathway target genes.…”

β-CATENIN is a positive prognostic marker for HPV-positive head and neck squamous cell carcinoma

“…This repression of Siah-1 by E6 and E7 indicates their direct role in the nuclear accumulation of β-CATENIN in HPV-associated OPSCC. Interestingly, blockade of the WBC pathway by a specific inhibitor of Creb-binding protein (CBP) has been demonstrated to be specifically effective in the HPV-positive HNSCC cell line SCC154 compared to the HPV-negative HNSCC cell line Cal27 (Brkic et al 2022). Moreover, MSAB, a small inhibitor of β-CATENIN, has been proven to have antineoplastic effects in HNSCC as well-supporting the oncogenic role of the WBC pathway in HNSCC (Maier et al 2023).…”