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Pten-null tumors cohabiting the same lung display differential AKT activation and sensitivity to dietary restriction

Natasha L Curry1, Mari Mino-Kenudson, Trudy G Oliver

  • 1Division of Endocrinology, Center for Basic and Translational Obesity Research, Boston , MA 02115, USA.

Cancer Discovery
|May 31, 2013
PubMed

Insights

PTEN loss alone doesn't guarantee PI3K/AKT pathway activation or dietary restriction resistance in lung tumors. ENTPD5 suppression can restore sensitivity by lowering IGF-IR levels.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • PTEN loss is a biomarker for PI3K/AKT pathway activation, often linked to cancer and dietary restriction resistance.
  • However, PTEN loss alone may not be sufficient to drive AKT activation and resistance in all tumor types.

Purpose of the Study:

  • To investigate the role of PTEN loss in AKT activation and dietary restriction resistance in lung cancer.
  • To identify factors that modulate PI3K/AKT pathway activity and treatment response in Pten-null lung tumors.

Main Methods:

  • Utilized a murine Pten-null Kras-driven lung cancer model with distinct tumor grades.
  • Analyzed AKT activity, growth factor receptor levels (IGF-IR), and ENTPD5 expression.
  • Investigated the effect of ENTPD5 suppression on tumor cell sensitivity in vitro and in vivo.

Main Results:

  • Pten loss resulted in both resistant (high-grade, bronchiolar) and sensitive (lower-grade, alveolar) tumors with differing AKT activity.
  • Normal bronchiolar cells exhibited higher IGF-IR and ENTPD5 levels, influencing tumor phenotypes.
  • ENTPD5 suppression reduced IGF-IR, sensitizing tumor cells to serum and dietary restriction.

Conclusions:

  • Tumor heterogeneity in response to PTEN loss is influenced by cell-autonomous factors like ENTPD5 and IGF-IR levels.
  • ENTPD5 is a potential therapeutic target to overcome dietary restriction resistance in lung cancer.
  • A subset of human non-small cell lung carcinomas (NSCLC) shows low AKT activity despite PTEN loss, suggesting complex regulatory mechanisms.

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