PI3K inhibition is a therapeutic strategy for solid cancers driven by PI3K catalytic subunit-α (PI3K-p110α; encoded by PIK3CA). Patients receiving inhibitors targeting PI3K-p110α experience transient hyperglycemia followed by hyperinsulinemia — the body’s response to keep blood glucose levels in check. These drugs targeting PI3K-p110α are less effective than lymphoma-approved drugs targeting PI3K-p110δ, a PI3K isoform that does not affect insulin signalling. A study published in Nature now shows that the glucose–insulin feedback in response to PI3K-p110α inhibition reactivates insulin signalling, thereby increasing glucose uptake but also limiting the effectiveness of the drug and promoting cancer progression.
Three strategies were tested to overcome the glucose–insulin feedback in PI3K inhibitor treated tumour-bearing mice, all known to increase insulin sensitivity through various mechanisms, and one of which relied on a change from a normal diet to a low-carbohydrate, high-fat diet. Prior to PI3K inhibitor treatment, mice were given metformin or sodium-glucose co-transporter 2 inhibitors (SGLT2i), or received the ketogenic diet. In these conditions, metformin did not lead to significant changes, though SGLT2i or the ketogenic diet reduced blood glucose and insulin levels compared with control mice. When analysing tumour growth in response to BYL-719 alone or in combination with metformin, SGLT2i or the ketogenic diet, only mice that received the ketogenic diet and BYL-719 had reduced glucose uptake in tumour tissue and increased survival. Preventing a spike in insulin levels was needed for the benefit in response to the ketogenic diet and BYL-719, because the growth of PI3K-p110α driven breast cancer allografts in mice, which was halted by the ketogenic diet and BYL-719, was rescued by the supplementation of exogenous insulin. Similar benefits in response to the ketogenic diet and PI3K inhibition using a range of inhibitors were observed in several patient-derived tumour xenograft models or syngeneic tumour allograft models of endometrial adenocarcinoma, bladder cancer and acute myeloid leukaemia (AML), in which PI3K-p110α signalling was driving growth. However, the therapeutic benefit of the ketogenic diet prior to PI3K blockade varied across models, and showed adverse effects when given alone in the AML model.
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