AUTHOR=Shailes Hannah , Tse Wai Yiu , Freitas Marta O. , Silver Andrew , Martin Sarah A. 

TITLE=Statin Treatment as a Targeted Therapy for APC-Mutated Colorectal Cancer

JOURNAL=Frontiers in Oncology

VOLUME=12

YEAR=2022

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2022.880552

DOI=10.3389/fonc.2022.880552

ISSN=2234-943X

ABSTRACT=<sec><title>Background</title><p>Mutations in the tumor suppressor gene Adenomatous Polyposis Coli (<italic>APC</italic>) are found in 80% of sporadic colorectal cancer (CRC) tumors and are also responsible for the inherited form of CRC, Familial adenomatous polyposis (FAP).</p></sec><sec><title>Methods</title><p>To identify novel therapeutic strategies for the treatment of <italic>APC</italic> mutated CRC, we generated a drug screening platform that incorporates a human cellular model of <italic>APC</italic> mutant CRC using CRISPR-cas9 gene editing and performed an FDA-approved drug screen targeting over 1000 compounds.</p></sec><sec><title>Results</title><p>We have identified the group of HMG-CoA Reductase (HMGCR) inhibitors known as statins, which cause a significantly greater loss in cell viability in the <italic>APC</italic> mutated cell lines and in <italic>in vivo APC</italic> mutated patient derived xenograft (PDX) models, compared to wild-type <italic>APC</italic> cells. Mechanistically, our data reveals this new synthetic lethal relationship is a consequence of decreased Wnt signalling and, ultimately, a reduction in the level of expression of the anti-apoptotic protein Survivin, upon statin treatment in the <italic>APC</italic>-mutant cells only. This mechanism acts <italic>via</italic> a Rac1 mediated control of beta-catenin.</p></sec><sec><title>Conclusion</title><p>Significantly, we have identified a novel synthetic lethal dependence between <italic>APC</italic> mutations and statin treatment, which could potentially be exploited for the treatment of <italic>APC</italic> mutated cancers.</p></sec>