The FDA-Approved Drug Pyrvinium Selectively Targets ER(+) Breast Cancer Cells with High INPP4B Expression

SIMPLE SUMMARY: Wnt/β-catenin signaling is hyperactivated in many human cancers including up to 50% of breast cancers. Although there has been significant progress in developing therapeutics that suppress Wnt/β-catenin signaling, particularly in colon cancer, the repurposing of FDA-approved therapeutics is likely to be a faster and more cost-effective method to target this pathway in human disease. Pyrvinium is an FDA-approved anthelmintic drug used to treat pinworms, which also suppresses Wnt/β-catenin signaling by activating the β-catenin destruction complex protein, CK1α. Here, we demonstrate that breast cancer cells with increased expression of the oncogene INPP4B, a PI3K regulator that promotes Wnt/β-catenin activation, are selectively sensitive to pyrvinium treatment in 2D and 3D culture. Therefore, Wnt inhibition using pyrvinium may be an effective strategy for treating human breast cancers with high INPP4B expression. ABSTRACT: The majority of breast cancers are estrogen receptor-positive (ER(+)), and endocrine therapies that suppress ER signaling are the standard-of-care treatment for this subset. However, up to half of all ER(+) cancers eventually relapse, highlighting a need for improved clinical therapies. The phosphoinositide phosphatase, INPP4B, is overexpressed in almost half of all ER(+) breast cancers, and promotes Wnt/β-catenin signaling, cell proliferation and tumor growth. Here, using cell viability assays, we report that INPP4B overexpression does not affect the sensitivity of ER(+) breast cancer cells to standard-of-care treatments including the anti-estrogen 4-hydroxytamoxifen (4-OHT) or the PI3Kα inhibitor alpelisib. Examination of four small molecule Wnt inhibitors revealed that ER(+) breast cancer cells with INPP4B overexpression were more sensitive to the FDA-approved drug pyrvinium and a 4-OHT-pyrvinium combination treatment. Using 3D culture models, we demonstrated that pyrvinium selectively reduced the size of INPP4B-overexpressing ER(+) breast cancer spheroids in the presence and absence of 4-OHT. These findings suggest that repurposing pyrvinium as a Wnt inhibitor may be an effective therapeutic strategy for human ER(+) breast cancers with high INPP4B levels.