GCN2 inhibition: The key to converting the dysregulated tumor metabolism and inducing potent antitumor responses
GCN2, or general control nonderepressible 2, is a stress response kinase that regulates the immune system and survival of tumor cells in the tumor microenvironment. Due to the abnormal vasculature of tumors, the blood supply is limited and results in a lack of oxygen and deprivation of nutrients, including amino acids. In human tumors, the GCN2 pathway is activated, and importantly, we have demonstrated that pharmacologic inhibition of GCN2 results in tumor growth reduction in preclinical mouse tumor models. Activation of the normal immune response is highly dependent on the availability of amino acids and other nutrients. GCN2 is a key cellular sensor and integrating node in T and other cells for amino acid and glucose limitation. Low levels of amino acids such as tryptophan, arginine and other amino acids lead to activation of GCN2. This triggers a cascade of cell signaling events in T cells leading to the inhibition of effector cell function and growth. GCN2, through this regulatory pathway, prevents immune cells from mounting an effective response when amino acid levels are in limited supply. Inactivation of GCN2 removes this regulatory block and allows effector cell proliferation and activation even under conditions of amino acid starvation similar to what may exist in tumors.