FDA-approved antivirals ledipasvir and daclatasvir downregulate the Src-EPHA2-Akt oncogenic pathway in colorectal and triple-negative breast cancer cells

Direct-acting antivirals ledipasvir (LDV) and daclatasvir (DCV) are widely used as part of combination therapies to treat Hepatitis C infections. Here we show that these compounds inhibit the proliferation, invasion, and colony formation of triple-negative MDA-MB-231 breast cancer cells, SRC-transduced SW620 colon cancer cells and SRC- transduced NIH3T3 fibroblasts. DCV also inhibits the expression of PDL-1, which is responsible for resistance to immunotherapy in breast cancer cells. The demonstrated low toxicity in many Hepatitis C patients suggests LDV and DCV could be used in combination therapies for cancer patients. At the molecular level, these direct-acting antivirals inhibit the phosphorylation of Akt and the ephrin type A receptor 2 (EPHA2) by destabilizing a Src-EPHA2 complex, although they do not affect the general kinase activity of Src. Thus, LDV and DCV could be effective drugs for Src-associated cancers without the inherent toxicity of classical Src inhibitors.