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MYC cooperates with AKT in prostate tumorigenesis and alters sensitivity to mTOR inhibitors

Nicola J Clegg1, Suzana S Couto, John Wongvipat

  • 1Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.

Plos One
|March 12, 2011
PubMed

Insights

MYC and PI3K-pathway alterations cooperate in prostate cancer progression. This cooperation leads to resistance to mTOR inhibitors, impacting treatment strategies for prostate cancer patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • MYC and phosphoinositide 3-kinase (PI3K) pathway deregulation are frequent in human prostate cancer.
  • A significant co-occurrence of MYC amplification and PI3K-pathway alteration was observed in 194 human prostate tumors.

Purpose of the Study:

  • To investigate the cooperative role of MYC and PI3K pathway alterations in prostate cancer progression.
  • To evaluate the therapeutic implications of this cooperation, particularly concerning mTOR inhibitor resistance.

Main Methods:

  • Generation of a bigenic mouse model (MPAKT/Hi-MYC) expressing activated human AKT1 and human MYC in the prostate.
  • Comparative analysis of the bigenic model with single-gene models (MPAKT and Hi-MYC) and wild-type mice.
  • Assessment of prostate intraepithelial neoplasia (mPIN) progression, microinvasion, stromal remodeling, and immune cell infiltration.
  • Evaluation of response to mTOR inhibitors in different mouse models.

Main Results:

  • The MPAKT/Hi-MYC model exhibited accelerated progression from mPIN to microinvasive disease, characterized by basement membrane disruption and significant stromal remodeling.
  • Bigenic mice showed infiltration of macrophages, B- and T-lymphocytes, mirroring inflammation in human prostate tumors.
  • Hi-MYC and MPAKT/Hi-MYC mice were resistant to mTOR inhibitors, unlike younger MPAKT mice.
  • Older MPAKT mice displayed reduced sensitivity to mTOR inhibition, suggesting acquired resistance mechanisms.

Conclusions:

  • Cooperation between MYC and PI3K pathway alterations accelerates prostate cancer progression and confers resistance to mTOR inhibitors.
  • Increased MYC expression, a common early event in prostate cancer, combined with PI3K-pathway alterations, has significant implications for treating human prostate cancers with these genetic lesions.
  • The findings suggest that mTOR inhibitors may be less effective in prostate cancers with co-occurring MYC and PI3K pathway alterations.

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