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p110γ deficiency protects against pancreatic carcinogenesis yet predisposes to diet-induced hepatotoxicity

Carolina Torres1, Georgina Mancinelli2, Jose Cordoba-Chacon3

  • 1Department of Medicine, Division of Gastroenterology and Hepatology, University of Illinois at Chicago, Chicago, IL 60612; ctp@ugr.es pgrippo@uic.edu.

Proceedings of the National Academy of Sciences of the United States of America
|July 4, 2019
PubMed

Insights

Targeting PI3K p110γ shows promise for pancreatic cancer therapy. However, its effectiveness may be limited in obese patients due to diet-induced signaling changes.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Pancreatic ductal adenocarcinoma (PDAC) presents significant therapeutic challenges due to poor survival rates and treatment resistance.
  • Phosphoinositide 3-kinase (PI3K) signaling pathways are critically involved in PDAC initiation and progression.
  • Emerging PI3K isoform-specific inhibitors offer potential therapeutic strategies for solid tumors.

Purpose of the Study:

  • To investigate the role of PI3K signaling, specifically the p110γ isoform, in the development and progression of pancreatic ductal adenocarcinoma.
  • To evaluate the therapeutic potential of targeting PI3K p110γ in combination with gemcitabine and assess the impact of diet and obesity on treatment efficacy.

Main Methods:

  • In vivo and in vitro studies utilizing mouse models of oncogenic Kras-driven PDAC.
  • Genetic ablation of the p110γ isoform and pharmacological inhibition of PI3K signaling.
  • Assessment of AKT signaling pathway activation, tumor growth, and hepatic damage.
  • Evaluation of treatment response in the context of a high-fat diet.

Main Results:

  • Increased PI3K signaling cooperates with oncogenic Kras to drive aggressive PDAC.
  • Overexpression of PI3K p110γ isoform promotes PDAC development via AKT signaling.
  • Selective blockade of p110γ sensitizes PDAC cells to gemcitabine in vitro and genetic ablation protects against Kras-induced tumorigenesis.
  • Diet-induced obesity upregulates p110 subunits; in high-fat diet settings, p110γ ablation is ineffective and leads to hepatic damage.

Conclusions:

  • PI3K p110γ plays a significant role in PDAC development and can be a therapeutic target.
  • Diet and obesity critically influence PI3K signaling and can abrogate the efficacy of p110γ-targeted therapies.
  • Therapeutic targeting of PI3K p110γ requires careful consideration, especially in obese patients, due to potential adverse effects and altered signaling.
Keywords:
AKT signalingPI3Kghepatotoxicityhigh-fat dietpancreatic cancer

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