Triple Negative Breast Cancer Inhibited With Migraine Drug

An international team of researchers executed screening studies to identify pharmacological compounds that trigger degradation of N-Ras which is a key protein that drives development of BLBC: flunarizine was highlighted as a candidate which was confirmed in subsequent in vitro studies to selectively block growth of BLBC cells, but not other types of breast cancer cells, and to inhibit tumor growth in an in vivo BLBC xenograft model.

There are 3 RAS genes in humans: H-, K-, and N-Ras; upwards of 30% of all tumors contain oncogenic RAS mutations, with K-Ras being the most frequently mutated gene in cancers; N-Ras also occur in certain cell types. Currently there are no drugs available to target Ras protein specifically, approaches are designed to reduce membrane affinity for Ras proteins, block Ras effector interaction, or inhibit activity of effector protein kinases; however tumors commonly develop resistance through mechanisms that are able to thwart off effectiveness of these approaches.

To investigate ways to control Ras post transcriptionally by proteolysis the team devised a screening strategy to identify and repurpose current FDA approved drugs that can induce Ras degradation. Calcium ion channel blocker flunarizine was identified by the assay. Subsequent studies indicated it to induced N-Ras degradation by autophagy, and in vitro studies showed it inhibited growth of BLBC cells; growth inhibition could be further enhanced by combining flunarizine with drugs that target other components of the N-Ras pathway. Final rounds of flunarizine therapy studies demonstrated it to reduce the growth of human BLBC tumors in mice.

Additional studies are required to determine why and how flunarizine therapy leads to N-Ras degradation in BLBC cells. The team suggests the study presents evidence that the autophagy pathway can be coerced by molecule inhibitors to degrade Ras as a strategy to treat cancer; and it has low toxicity that should be investigated for further uses against cancer. The study also to helps validate the use of screening approaches to identify and repurpose existing compounds in the fight against cancer.