Abstract KN01: Keynote Lecture: PI 3-kinase links obesity, insulin resistance, and cancer

Abstract

Abstract Phosphoinositide 3-kinase (PI3K) is activated by insulin and other growth factors to mediate cell growth. The PI3K enzyme encoded by the PIK3CA gene is one of the most frequently mutated oncogenes in human cancer. This same enzyme mediates insulin responses in liver, muscle, fat, and other tissues. The most common mutations in this gene enhance the ability of PI3K to bind to the insulin receptor substrates, IRS1 and IRS2, and thereby enhance the ability of PI3K to be activated by insulin and IGF1. This observation raises the possibility that elevated levels of serum insulin could enhance the growth of tumors that express the insulin receptor, especially when the tumor expresses a mutant form of PIK3CA. Consistent with this idea, retrospective studies have shown that cancers that correlate with obesity and insulin resistance (conditions where serum insulin levels are high), such as endometrial, breast, and colorectal cancers, frequently have activating mutations in PIK3CA. These observations suggest a model in which tumors with mutations in PIK3CA are highly sensitized to insulin-dependent growth and that the elevated serum insulin levels in individuals with insulin resistance in liver, muscle, and fat promote anabolic metabolism in the tumor. This condition would allow the tumor to take up glucose more readily than muscle or fat in insulin-resistant individuals. We have generated mouse models to interrogate the role of PI3Ks in metabolic control and in the generation of cancers. These studies indicate that inhibitors of PI3Ks could be effective in treating cancers in specific mutational backgrounds. More than 20 PI3K inhibitors that target the gene product of PIK3CA have entered clinical trials for treating solid cancers. Although these inhibitors look promising, a variety of toxicities have created challenges. Some of the toxicities, such as hyperglycemia, are on target since inhibition of the PIK3CA gene product is expected to cause insulin resistance. Importantly, the acute insulin resistance that occurs in response to PI3K inhibitors not only raises serum glucose levels, but also induces insulin release from the pancreas, which raises insulin levels. As discussed above, the increased serum insulin has the potential to activate PI3K in the tumor, and it is possible that very high insulin levels could reactivate PI3K in the tumor despite the presence of a PI3K inhibitor. We have interrogated this possibility in a wide variety of mouse models of cancer and find that the high serum insulin levels that appear following an oral dose of a variety of PI3K inhibitors in both human and mouse are sufficient to activate the PI3K-mTOR signaling pathway. We have utilized multiple therapeutic interventions in attempts to prevent this rebound of insulin-dependent PI3K reactivation in tumors, including metformin, a sodium-glucose co-transporter inhibitor, and a ketogenic diet. We found that the ketogenic diet is more effective than other therapies at lowering serum insulin levels during PI3K treatment. Importantly, combining a ketogenic diet with a PI3K inhibitor causes a dramatic shrinkage of tumors compared to either therapy alone. Citation Format: Lewis C. Cantley. Keynote Lecture: PI 3-kinase links obesity, insulin resistance, and cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr KN01.