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PI3K/AKT/mTOR pathway is activated after imatinib secondary resistance in gastrointestinal stromal tumors (GISTs)

Jian Li1, Yunzhi Dang, Jing Gao

  • 1Laboratory of Carcinogenesis and Translational Research for the Ministry of National Education, Department of GI Oncology, Peking University School of Oncology, Beijing Cancer Hospital & Institute, 52 Fucheng Road, Haidian District, Beijing, 100142, China.

Medical Oncology (Northwood, London, England)
|March 12, 2015
PubMed

Insights

Activation of the Phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of the rapamycin (mTOR) pathway increases with imatinib resistance in gastrointestinal stromal tumors (GIST). AKT/mTOR activation is key, with PI3K activation potentially signaling early resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Imatinib resistance is a significant challenge in treating gastrointestinal stromal tumors (GIST).
  • The Phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of the rapamycin (mTOR) pathway is implicated in cancer progression and drug resistance.
  • Previous studies have not fully elucidated the dynamic changes in PI3K/AKT/mTOR pathway signaling following imatinib treatment in GIST.

Purpose of the Study:

  • To investigate the alterations in the PI3K/AKT/mTOR pathway signaling in GIST samples before and after imatinib treatment.
  • To determine the correlation between PI3K/AKT/mTOR pathway activation and the development of imatinib resistance in GIST.
  • To identify key components of the PI3K/AKT/mTOR pathway that contribute to secondary imatinib resistance.

Main Methods:

  • Analysis of 111 GIST samples from 91 patients, including 20 paired samples before and after imatinib treatment.
  • Immunohistochemical staining for p-KIT, PTEN, PI3K, p-AKT, p-4EBP1, and p-S6RP.
  • Comparison of pathway activation status between imatinib-sensitive, primary resistant, and secondary resistant GIST, as well as pre- and post-treatment samples.

Main Results:

  • AKT/mTOR pathway activation was significantly higher in secondary resistant GIST (53.1%) compared to sensitive (27.1%) and primary resistant (33.3%) GIST.
  • In paired samples, PI3K activation shifted from inactive to active in 8 patients with effective imatinib and 12 patients with secondary resistance.
  • AKT/mTOR activation shifted from inactive to active in 6 of 12 patients who developed secondary resistance, suggesting it's a crucial factor.

Conclusions:

  • The PI3K/AKT/mTOR pathway becomes partially activated following secondary imatinib resistance in GIST.
  • AKT/mTOR activation appears to be a more critical driver of secondary resistance than PI3K activation.
  • PI3K activation may represent an early event in the development of secondary imatinib resistance in GIST.

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