Cochet, C. | bioRxiv Science

bioRxiv2023

COL7A1 expression improves prognosis prediction for patients with clear cell renal cell carcinoma atop of stage

Clear cell renal cell carcinoma (ccRCC) accounts for 75% of kidney cancers. Due to the high recurrence rate, and treatment options that come with high costs and potential side effects correct prognosis of patient survival is essential for the successful and effective treatment of patients. Novel biomarkers could play an important role in the assessment of the overall survival of patients. COL7A1 encodes for collagen type VII, a constituent of the basal membrane. COL7A1 is associated with survival in many cancers; however, the prognostic value of COL7A1 expression as a standalone biomarker in ccRCC has not been investigated. We used Kaplan-Meier curves and Cox proportional hazards model to investigate the prognostic value of COL7A1, as well as Gene Set Enrichment Analysis to investigate genes that are co-expressed with COL7A1. COL7A1 expression was used to stratify patients into four groups of expression, where the 5-year survival probability of each group was 72.4%, 59.1%, 34.15%, and 8.6% in order of increasing expression. Additionally, COL7A1 expression was successfully used to further divide patients of each stage and histological grade into groups of high and low risk. Similar results were obtained in independent cohorts. In-vitro knockdown of COL7A1 expression significantly impacted ccRCC cells ability to migrate and proliferate. To conclude, we identified COL7A1 as a new prognosis marker that can stratify ccRCC patients.

cancer biology↗

bioRxiv2022

AB668, a novel highly selective protein kinase CK2 inhibitor with a distinct anti-tumor mechanism as compared to CX-4945 and SGC-CK2-1

Although the involvement of protein kinase CK2 in cancer is well-documented, there is a need for selective CK2 inhibitors suitable for investigating CK2 specific roles in cancer-related biological pathways and further explore its therapeutic potential. Here we have discovered AB668, a new bivalent inhibitor that binds both at the ATP site and an allosteric D pocket unique to CK2. The molecule inhibits CK2 activity with an outstanding selectivity over other kinases. Using caspase activation assay, live-cell imaging and transcriptomic analysis, we have compared the effects of this bivalent inhibitor to the non-selective ATP-competitive inhibitor CX-4945 that reached clinic and to the selective ATP-competitive SGC-CK2-1 molecule. Our results show that in contrast to CX-4945 or SGC-CK2-1, AB668 has a distinct mechanism of action regarding its anti-cancer activity, inducing apoptotic cell death and stimulating distinct biological pathways in several cancer cell lines while sparing healthy cells. Our data suggest that targeting a cryptic CK2 D pocket validates an allosteric approach to targeting CK2 and provides a starting point for creating drug-like CK2 inhibitors for aggressive cancers.

biochemistry↗