Targeting MSH2-MSH6 heterodimer in treating basal-like breast cancer

To identify novel therapeutic targets for basal-like breast cancer (BLBC) subtype, we investigated several DNA repair mechanisms associated with maintenance of high genomic instability for cell survival in cancer cells. We identified that the mismatch repair proteins, MSH2 and MSH6 (referred to as MSH2/6 hereafter), are highly elevated across BLBC samples. High expression level of MSH2/6 in BLBC is associated with worse prognosis and survivability for patients. Therefore, we knocked out MSH2 in BLBC cell lines and performed in vivo xenograft and syngeneic mice model studies to find significant attenuation of tumor growth in MSH2 KO group. Also, MSH2-deficient BLBC cells have increased rate of new mutations. Additionally, we tested the efficacy of conventional chemotherapeutics and radiation treatment that would further tip the genomic instability in MSH2-deficient BLBC cells towards cell death, but found them to be ineffective. Next, we performed high-throughput screening of 1280 FDA-approved compounds to discover that calcium channel blockers preferentially kill MSH2-deficient BLBC cells. This was likely due to association of significantly mutated pathways that involved calcium ion binding and calmodulin binding sites. Here we provide evidence of an alternative therapeutic strategy targeting DNA repair genes in BLBC patients utilizing bioinformatics analysis, high-throughput drug screening, in vitro,and vivoexperimentalmodels.