Cross-platform Screening for Novel Fluvastatin and Kinase Inhibitor Co-therapies in Cancer Cell Lines

Statins are widely used to manage hypercholesterolemia, and clinical trials have demonstrated that statins as monotherapies are effective anticancer agents in some patients. We aim to identify combination treatments that will expand the anticancer benefit of statins. We hypothesize that screening cancer cell lines with a genomic shRNA library and a small-molecule library will identify novel compounds to use in co-therapies with fluvastatin. A pooled shRNA dropout screen was performed to find genomic targets to inhibit alongside fluvastatin, which revealed several kinase targets as dropouts. This suggested that knocking down specific kinases can potentiate fluvastatin-induced cell death. To identify known kinase inhibitors that interact with fluvastatin to elicit cancer cell kill, we screened with a library of 320 kinase inhibitors, which revealed several putative hits. We anticipate that continued validation of candidates from both screens will lead to the identification of novel anticancer statin-based drug cocktails.MAS