Lipid metabolic reprogramming as an emerging mechanism of resistance to kinase inhibitors in breast cancer.

Breast cancer is one of the leading causes of death in women in the United States. In general, patients with breast cancer undergo surgical resection of the tumor and/or receive drug treatment to kill or suppress the growth of cancer cells. In this regard, small molecule kinase inhibitors serve as an important class of drugs used in clinical and research settings. However, the development of resistance to these compounds, in particular HER2 and CDK4/6 inhibitors, often limits durable clinical responses to therapy. Emerging evidence indicates that PI3K/AKT/mTOR pathway hyperactivation is one of the most prominent mechanisms of resistance to many small molecule inhibitors as it bypasses upstream growth factor receptor inhibition. Importantly, the PI3K/AKT/mTOR pathway also plays a pertinent role in regulating various aspects of cancer metabolism. Recent studies from our lab and others have demonstrated that altered lipid metabolism mediates the development of acquired drug resistance to HER2-targeted therapies in breast cancer, raising an interesting link between reprogrammed kinase signaling and lipid metabolism. It appears that, upon development of resistance to HER2 inhibitors, breast cancer cells rewire lipid metabolism to somehow circumvent the inhibition of kinase signaling. Here, we review various mechanisms of resistance observed for kinase inhibitors and discuss lipid metabolism as a potential therapeutic target to overcome acquired drug resistance.