Abstract
Simple SummaryMetastatic urothelial cell carcinoma (UCC) is a significant public health burden with a median survival estimated at about 15 months. The use of immunotherapy with immune checkpoint inhibitors has greatly improved outcomes but only benefits a minority (~20%) of patients. In this review we discuss the evidence showing how a key molecular pathway known as Wnt/β-catenin signaling can be a driver of immunotherapy resistance and how these insights can serve as lessons for improving future treatment of urothelial carcinoma. Urothelial cell carcinoma (UCC) is a significant public health burden. It accounts for approximately 90 percent of all bladder cancers with an estimated 200,000 annual deaths globally. Platinum based cytotoxic chemotherapy combinations are the current standard of care in the frontline setting for metastatic UCC. Even with these treatments the median overall survival is estimated to be about 15 months. Recently, immune checkpoint inhibitors (ICIs) have demonstrated superior clinical benefits compared to second line chemotherapy in UCC treatment. However only a minority of patients (~20%) respond to ICIs, which highlights the need to better understand the mechanisms behind resistance. In this review, we (i) examine the pathophysiology of Wnt/β-catenin signaling, (ii) discuss pre-clinical evidence that supports the combination of Wnt/β-catenin inhibitors and ICI, and (iii) propose future combination treatments that could be investigated through clinical trials.
Highlights
Urothelial cell carcinoma (UCC) is the most common malignancy of the urinary system.It accounts for approximately 90 percent of all bladder cancers with an estimated 200,000 annual deaths globally [1,2]
Immune checkpoint inhibitors (ICIs) have demonstrated superior clinical benefits compared to second line chemotherapy in UCC treatment [7,8]
The investigators found that the isogenic colon cancer cell lines (HCT116 investigators found that the isogenic colon cancer cell lines (HCT116 and Hke-3 cells) and Hke-3 cells) with mutated active β-catenin when cultured with TAMs would produce with mutated active β-catenin when cultured with TAMs would produce more snail promore snail protein, which is a known Wnt/β-catenin signaling target gene and driver of tein, which is a known Wnt/β-catenin signaling target gene and driver of tumor mesenchytumor mesenchymal transition [50]. These results suggested that the increased Wnt/βmal transition [50]. These results suggested that the increased Wnt/β-catenin signaling from catenin signaling from the TAMs could induce snail gene expression and drive a tumor the TAMs could induce snail gene expression and drive a tumor mesenchymal transition mesenchymal transition phenotype [50]
Summary
Urothelial cell carcinoma (UCC) is the most common malignancy of the urinary system. It accounts for approximately 90 percent of all bladder cancers with an estimated 200,000 annual deaths globally [1,2]. It has been noted that those patients who respond to ICIs can often maintain an impressive durable response lasting more than 14–15 months [7,8] This phenomenon has been observed across numerous cancer subtypes [10], highlighting the need to better understand the mechanisms behind ICI resistance. We will (i) examine the pathophysiology of Wnt/β-catenin signaling, (ii) discuss pre-clinical evidence that supports the combination of Wnt/β-catenin inhibitors and ICI, and (iii) propose future combination treatments that could be investigated through. The majority studiesthat investigating the cell surfaceapy and within the cytoplasm This pathway mediates an array of biological resistance mechanisms have been done in non-UCC studies; as a result, the proposals functions, including cell fateextrapolate decisions during embryonic equiin this review data derived fromdevelopment, both urothelialstem andcell non-urothelial studies. Β-catenin-dependent, Wnt signaling is one of the primary sources of
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
