Diet–Microbiome Interactions Limit PI3K Inhibitor Efficacy in Cancer Available to Purchase

Diet is emerging as a complement to cancer therapy, with evidence that certain dietary interventions can slow tumor growth and enhance drug efficacy. The ketogenic diet, known for its carbohydrate restriction, has been shown to enhance the effects of phosphatidylinositol 3-kinase (PI3K) inhibitors in suppressing pancreatic tumors in mouse models. This synergy was previously attributed to reduced insulin signaling, which prevents PI3K reactivation in tumors. However, recent findings from Roichman and colleagues suggests the story is more complex. Beyond macronutrients, phytochemicals—plant-derived bioactive compounds—represent an underexplored dietary factor that could affect cancer drug response.  The gut microbiome can metabolize these phytochemicals into secondary metabolites, but their impact on drug response remains unclear. To investigate this, Rochman and colleagues used a carbohydrate-rich purified diet (CPD) to isolate the effects of unrefined chow ingredients. Remarkably, mice on the CPD showed similar tumor suppression and increased PI3K inhibitor efficacy as those on the ketogenic diet. Additionally, depleting the gut microbiome with antibiotics restored tumor suppression and PI3K inhibitor efficacy in chow-fed mice, pinpointing the microbiome as a critical mediator of reduced drug effectiveness. Mechanistic studies revealed that both purified diets and antibiotic treatment suppressed liver expression of cytochrome P450 enzymes, including Cyp3a, which is involved in drug metabolism. Inhibiting CYP3A restored the PI3K inhibitor efficacy in the chow-fed mice, suggesting that CYP3A-mediated drug metabolism reduces the bioavailability of the PI3K inhibitor. Further analysis identified soy, a major chow component rich in phytochemicals, as a key driver of reduced PI3K inhibitor activity. Specifically, the team identified soyasaponin Ab, a microbiome-derived metabolite, as the compound activating the nuclear receptor PXR and inducing Cyp3a expression. This work highlights the critical role of diet-microbiome interactions in shaping cancer drug response and offers a new perspective on why insulin-targeted strategies may fall short in enhancing PI3K inhibitor efficacy.  

Roichman A, Zuo Q, Hwang S, Lu W, Cordova RA, MacArthur MR, Boyer JA, et al. Microbiome metabolism of dietary phytochemicals controls the anticancer activity of PI3K inhibitors. Cell 2025;188:3065–80.

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