A small molecule (1) with overlapping affinity for two
microRNA (
miRNA) precursors was used to inform design of a dimeric compound (2) selective for one of the
miRNAs. In particular, 2 selectively targets the microRNA(miR)-515 hairpin precursor to inhibit production of miR-515 that represses
sphingosine kinase 1 (SK1), a key
enzyme in the biosynthesis of
sphingosine 1-phosphate (S1P). Application of 2 to
breast cancer cells enhanced SK1 and S1P levels, triggering a migratory phenotype. Knockout of SK1, forced overexpression of miR-515, and application of a small molecule SK1 inhibitor all ablated 2's effect on phenotype, consistent with its designed mode of action. Target profiling studies via Chem-
CLIP showed that 2 bound selectively to the miR-515 hairpin precursor in cells. Global neoprotein synthesis upon addition of 2 to MCF-7
breast cancer cells demonstrated 2's selectivity and upregulation of
cancer-associated
proteins regulated by S1P. The most upregulated
protein was
human epidermal growth factor receptor 2 (ERBB2/HER2), which is regulated by the SK1/S1P pathway and is normally not expressed in MCF-7 cells. Like
triple negative breast cancer (TNBC) cells, the lack of HER2 renders them insusceptible to
Herceptin and its
antibody-drug conjugate Kadcyla. In addition to proteomics, an
RNA-seq study supports that 2 has limited off target effects and other studies support that 2 is more selective than an
oligonucleotide. We therefore hypothesized that 2 could sensitize MCF-7 cells to anti-HER2
therapies. Indeed, application of 2 sensitized cells to
Herceptin. These results were confirmed in two other cell lines that express miR-515 and are HER2-, the
hepatocellular carcinoma cell line HepG2 and the TNBC line MDA-MB-231. Importantly, normal breast epithelial cells (MCF-10A) that do not express miR-515 are not affected by 2. These observations suggest a
precision medicine approach to sensitize HER2-
cancers to approved anticancer medicines. This study has implications for broadening the therapeutic utility of known targeted
cancer therapeutics by using a secondary targeted approach to render otherwise insensitive cells, sensitive to a targeted therapeutic.