2. Academic Validation
  3. Microbiome metabolism of dietary phytochemicals controls the anticancer activity of PI3K inhibitors

Microbiome metabolism of dietary phytochemicals controls the anticancer activity of PI3K inhibitors

  • Cell. 2025 May 29;188(11):3065-3080.e21. doi: 10.1016/j.cell.2025.04.041.
Asael Roichman 1,  Qianying Zuo 2,  Sunghoon Hwang 3,  Wenyun Lu 1,  Ricardo A Cordova 1,  Michael R MacArthur 1,  Jacob A Boyer 4,  Sarah J Mitchell 4,  Jesse Powers 5,  Sophia A Koval 3,  Craig J Hunter 6,  Jamie Rijmers 7,  Rolf-Peter Ryseck 1,  Jenna E AbuSalim 8,  Seema Chatterjee 3,  Won Dong Lee 6,  Xincheng Xu 1,  Xi Xing 6,  Zihong Chen 1,  Xianfeng Zeng 6,  Siddharth Marwaha 3,  Matthew J McBride 6,  Jessie Y Guo 5,  Yibin Kang 2,  Mohamed S Donia 3,  Joshua D Rabinowitz 9
Affiliations

Affiliations

  • 1 Department of Chemistry, Princeton University, Princeton, NJ 08544, USA; Lewis-Sigler Institute of Integrative Genomics, Princeton University, Princeton, NJ, USA; Ludwig Institute for Cancer Research, Princeton Branch, Princeton, NJ, USA.
  • 2 Ludwig Institute for Cancer Research, Princeton Branch, Princeton, NJ, USA; Department of Molecular Biology, Princeton University, Princeton, NJ, USA.
  • 3 Department of Molecular Biology, Princeton University, Princeton, NJ, USA.
  • 4 Ludwig Institute for Cancer Research, Princeton Branch, Princeton, NJ, USA.
  • 5 Rutgers Cancer Institute, New Brunswick, NJ, USA.
  • 6 Department of Chemistry, Princeton University, Princeton, NJ 08544, USA; Lewis-Sigler Institute of Integrative Genomics, Princeton University, Princeton, NJ, USA.
  • 7 Division of Pharmacology, the Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands.
  • 8 Lewis-Sigler Institute of Integrative Genomics, Princeton University, Princeton, NJ, USA; Ludwig Institute for Cancer Research, Princeton Branch, Princeton, NJ, USA; Department of Molecular Biology, Princeton University, Princeton, NJ, USA.
  • 9 Department of Chemistry, Princeton University, Princeton, NJ 08544, USA; Lewis-Sigler Institute of Integrative Genomics, Princeton University, Princeton, NJ, USA; Ludwig Institute for Cancer Research, Princeton Branch, Princeton, NJ, USA. Electronic address: joshr@princeton.edu.
PMID: 40393457 DOI: 10.1016/j.cell.2025.04.041
Abstract

Phosphatidylinositol 3-kinase (PI3K) signaling is both the effector pathway of Insulin and among the most frequently activated pathways in human Cancer. In murine Cancer models, the efficacy of PI3K inhibitors is dramatically enhanced by a ketogenic diet, with a proposed mechanism involving dietary suppression of Insulin. Here, we confirm profound diet-PI3K Anticancer synergy but show that it is, surprisingly, unrelated to diet macronutrient composition. Instead, the diet-PI3K interaction involves microbiome metabolism of ingested phytochemicals. Specifically, murine ketogenic diet lacks the complex spectrum of phytochemicals found in standard chow, including the soy phytochemicals soyasaponins. We find that soyasaponins are converted by the microbiome into inducers of hepatic Cytochrome P450 enzymes, and thereby lower PI3K Inhibitor blood levels and Anticancer activity. A high-carbohydrate, low-phytochemical diet synergizes with PI3K inhibition to treat Cancer in mice, as do Antibiotics that curtail the gut microbiome. Thus, diet impacts Anticancer drug activity through phytochemical-microbiome-liver interactions.

Keywords

PI3Ki; breast cancer; cytochrome P450; diet and cancer treatment; gut-liver axis; microbiome metabolites; pancreatic cancer; pharmacokinetics; phytochemicals; soyasaponins.

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