Resorting the function of the colorectal cancer gatekeeper adenomatous polyposis coli

Abstract

As a large number of cancers are caused by nonsense mutations in key genes, read‐through of these mutations to restore full‐length protein expression is a potential therapeutic strategy. Mutations in the adenomatous polyposis coli (APC) gene initiate the majority of both sporadic and hereditary colorectal cancers (CRC) and around 30% of these mutations are nonsense mutations. Our goal was to test the feasibility and effectiveness of APC nonsense mutation read‐through as a potential chemo‐preventive therapy in Familial Adenomatous Polyposis (FAP), an inherited CRC syndrome patients. Ten FAP patients harboring APC nonsense mutations were treated with the read‐through inducing antibiotic erythromycin for 4 months. Endoscopic assessment of the adenomas was performed at baseline, after 4 and after 12 months. Adenoma burden was documented in terms of adenoma number, maximal polyp size and cumulative polyp size per procedure. Tissue samples were collected and subjected to molecular and genetic analyses. Our results show that in the majority of patients the treatment led to a decrease in cumulative adenoma burden, median reduction in cumulative adenoma size and median reduction in adenoma number. Molecular and genetic analyses of the adenomas revealed that the treatment led to a reduced number of somatic APC mutations, reduced cellular proliferation and restoration of APC tumor‐suppressing activity. Together, our findings show that induced read‐through of APC nonsense mutations leads to promising clinical results and should be further investigated to establish its therapeutic potential in FAP and sporadic CRCs harboring nonsense APC mutations.

A CRISPR knockout screen reveals new regulators of canonical Wnt signaling

“…To rule out a nonspecific effect on cell proliferation and confirm that the increased Cyclin-D1 levels observed upon DHX29 KO can be specifically attributed to Wnt signaling regulation, we tested the levels of proliferation in this cell line. Proliferation was tested using Ki-67, a proliferative marker strongly linked to cell cycle control [ 19 ]. NT1 and DHX29 KO cell lines were fixed and stained with a Ki-67 specific antibody (Fig.…”

Adenomatous polyposis coli in cancer and therapeutic implications

“…In a clinical trial, ten patients with FAP and APC nonsense mutations were given erythromycin for 4 months and had endoscopies at baseline, 4 months, and 12 months after treatment. 149 Results indicated that the number of adenomas and cumulative and maximal polyp size decreased. Tissue samples were also collected for assessment and were then molecularly and genetically analyzed.…”

“…Treatment not only reduced the number of somatic APC mutations, but also restored APC gene function and decreased cellular proliferation. 149 …”

Selective toxicity of antibacterial agents—still a valid concept or do we miss chances and ignore risks?

“…If read-through in eukaryotes is due to an interference with mitochondrial functions only has not been addressed. Nevertheless, a clinical study investigating the efficacy of erythromycin treatment for read-through of APC gene stop codon mutations in familial adenomatous polyposis has been initiated [247] and the impact of macrolides on stop codon read-through has been proven in proand eukaryotic species as well as patients (Table 1) [242,[248][249][250][251][252][253].…”