Pictilisib and nutrient stress synergize to induce methuosis via PI(4,5)P2-dependent macropinocytic dysregulation in cancer cells

  • Cell Death Dis. 2026 Jun 16. doi: 10.1038/s41419-026-08994-6.
Xuefei Wang  #  1 ,  Xiaolin Sang  #  2 ,  Yuemei Wen  3 ,  Xingming Liao  3 ,  Jiao Liu  1 ,  Tiezheng Zheng  1  3 ,  Tianming Xing  3 ,  Min Wang  1 ,  Dong An  1 ,  Xining Zhang  1 ,  Xiuling Li  4  5 ,  Xinmiao Liang  6  7 ,  Pixu Liu  8  9 ,  Hailing Cheng  10  11
Affiliations
  • 1. Cancer Institute, The Second Hospital of Dalian Medical University, Dalian, Liaoning, China.
  • 2. Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
  • 3. Institute of Cancer Stem Cell, Dalian Medical University, Dalian, Liaoning, China.
  • 4. Key Laboratory of Phytochemistry and Natural Medicines, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, Liaoning, China. [email protected].
  • 5. Ganjiang Chinese Medicine Innovation Center, Nanchang, Jiangxi, China. [email protected].
  • 6. Key Laboratory of Phytochemistry and Natural Medicines, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, Liaoning, China. [email protected].
  • 7. Ganjiang Chinese Medicine Innovation Center, Nanchang, Jiangxi, China. [email protected].
  • 8. Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China. [email protected].
  • 9. Institute of Cancer Stem Cell, Dalian Medical University, Dalian, Liaoning, China. [email protected].
  • 10. Cancer Institute, The Second Hospital of Dalian Medical University, Dalian, Liaoning, China. [email protected].
  • 11. Dalian Lingshui Bay Laboratory, Dalian, Liaoning, China. [email protected].
  • # Contributed equally.
PMID: 42303628 DOI: 10.1038/s41419-026-08994-6
Abstract

Aberrant phosphatidylinositol 3-kinase (PI3K) activation drives many cancers, but PI3K inhibitors like Pictilisib often induce cytostasis rather than cytotoxicity, limiting their therapeutic potential. Here we demonstrate that PI3K inhibition combined with nutrient stress triggers methuosis, a non-apoptotic form of programmed cell death characterized by dysregulated macropinosomes. This response occurs selectively in PI3K-aberrant Cancer cells that maintain macropinocytic uptake despite PI3K inhibition. Methuosis-associated vacuoles originate from macropinosomes that retain endosomal markers but fail to undergo lysosomal fusion. Active macropinocytic uptake is essential for methuosis, as demonstrated by suppression with EIPA and Bafilomycin A1, whereas the Akt Inhibitor MK2206 has no effect, establishing that direct PI3K inhibition, rather than Akt signaling, is required. Mechanistically, PI3K blockade prevents conversion of phosphatidylinositol (4,5)-bisphosphate (PI(4,5)P2) to phosphatidylinositol (3,4,5)-trisphosphate (PI(3,4,5)P3) causing PI(4,5)P2 to accumulate on internalizing macropinosomal membranes. This aberrant PI(4,5)P2 enrichment impairs ion channel function across multiple channel families, disrupting intracellular osmotic balance. Ion dysregulation triggers aquaporin-1-mediated water influx, driving catastrophic vacuolar expansion and cell death. Although Pictilisib activates pro-survival Autophagy, this fails to prevent methuosis-mediated cytotoxicity. In xenograft models, dietary restriction synergizes with Pictilisib to suppress tumor growth, correlating with pronounced intratumoral vacuolization. These findings reveal that combining PI3K inhibition with nutrient restriction converts cytostatic responses into methuosis-driven cytotoxicity via PI(4,5)P2-dependent macropinocytic dysregulation, providing a rational pharmacologic-dietary strategy to enhance PI3K-targeted Cancer efficacy.

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