Resorting the function of the colorectal cancer gatekeeper adenomatous polyposis coli

Revital Kariv*, Michal Caspi, Naomi Fliss-Isakov, Yamit Shorer, Yarden Shor, Guy Rosner, Eli Brazowski, Gil Beer, Shlomi Cohen, Rina Rosin-Arbesfeld

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)1064-1074
Number of pages11
JournalInternational Journal of Cancer
Volume146
Issue number4
DOIs
StatePublished - 15 Feb 2020

Keywords

  • adenomatous polyposis coli
  • colorectal cancer
  • familial adenomatous polyposis
  • nonsense mutation read-through

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