Suppression of insulin feedback enhances the efficacy of PI3K inhibitors

Mutations in PIK3CA, encoding the insulin-activated phosphoinositide-3-kinase (PI3K), and loss of function mutations in PTEN, a phosphatase that degrades the phosphoinositide lipids generated by PI3K, are among the most frequent events in human cancers(1,2). Yet, pharmacological inhibition of PI3K has resulted in variable clinical responses, raising the possibility of an inherent mechanism of resistance. Since the PIK3CA-encoded enzyme, p110α, mediates virtually all cellular responses to insulin, targeted inhibition of this enzyme disrupts glucose metabolism in multiple tissue types. For example, blocking insulin signaling promotes glycogen breakdown in the liver and prevents glucose uptake in the skeletal muscle and adipose tissue, resulting in transient hyperglycemia that occurs within a few hours of PI3K inhibition. The effect is usually transient because compensatory insulin release from the pancreas (i.e. insulin feedback) restores normal glucose homeostasis3. However, the hyperglycemia may be exacerbated or prolonged in patients with any degree of insulin resistance and, in these cases, requires discontinuation of therapy(3–6). We hypothesized that insulin feedback induced by PI3K inhibitors may be reactivating the PI3K-mTOR signaling axis in tumors, compromising their effectiveness(7,8). Here, we show in several model tumors, that systemic glucose-insulin feedback caused by targeted inhibition of this pathway is sufficient to activate PI3K signaling, even in the presence of PI3K inhibitors. We demonstrate that this insulin feedback can be prevented using dietary or pharmaceutical approaches, which greatly enhance the efficacy/toxicity ratios of these compounds. These findings have direct clinical implications for the multiple p110α inhibitors that are in clinical trials and provide a means to significantly increase treatment efficacy for patients with a myriad of tumor types.