Autophagy Correlates with the Therapeutic Responsiveness of Malignant Pleural Mesothelioma in 3D Models

PLoS One. 2015 Aug 18;10(8):e0134825. doi: 10.1371/journal.pone.0134825. eCollection 2015.


Malignant pleural mesothelioma is a highly chemoresistant solid tumor. We have studied this apoptotic resistance using in vitro and ex vivo three-dimensional models, which acquire a high level of chemoresistance that can be reduced by PI3K/mTOR inhibitors. Here, we investigate the activity of GDC-0980, a novel dual PI3K/mTOR inhibitor, which has been proposed to be effective in mesothelioma. In this work, we aimed to identify mechanisms and markers of efficacy for GDC-0980 by utilizing 3D models of mesothelioma, both in vitro multicellular spheroids and ex vivo tumor fragment spheroids grown from patient tumor samples. We found that a subset of mesothelioma spheroids is sensitive to GDC-0980 alone and to its combination with chemotherapy. Unexpectedly, this sensitivity did not correlate with the activation of the Akt/mTOR pathway. Instead, sensitivity to GDC-0980 correlated with the presence of constitutive ATG13 puncta, a feature of autophagy, a cellular program that supports cells under stress. In tumor fragment spheroids grown from 21 tumors, we also found a subset (n = 11) that was sensitive to GDC-0980, a sensitivity that also correlated with the presence of ATG13 puncta. Interference with autophagy by siRNA of ATG7, an essential autophagic protein, increased the response to chemotherapy, but only in the sensitive multicellular spheroids. In the spheroids resistant to GDC-0980, autophagy appeared to play no role. In summary, we show that GDC-0980 is effective in mesothelioma 3D models that display ATG13 puncta, and that blockade of autophagy increases their response to chemotherapy. For the first time, we show a role for autophagy in the response to chemotherapy of 3D models of mesothelioma and propose ATG13 as a potential biomarker of the therapeutic responsiveness of mesothelioma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Autophagy / drug effects*
  • Autophagy-Related Protein 7
  • Autophagy-Related Proteins
  • Biomarkers / metabolism
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology*
  • Cell Line, Tumor
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / metabolism
  • Mesothelioma / drug therapy*
  • Mesothelioma / metabolism
  • Mesothelioma, Malignant
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Pyrimidines / pharmacology*
  • Signal Transduction / drug effects
  • Spheroids, Cellular / drug effects
  • Spheroids, Cellular / metabolism
  • TOR Serine-Threonine Kinases / metabolism
  • Ubiquitin-Activating Enzymes / metabolism


  • 1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno(3,2-d)pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one
  • ATG13 protein, human
  • Adaptor Proteins, Signal Transducing
  • Autophagy-Related Proteins
  • Biomarkers
  • Bridged Bicyclo Compounds, Heterocyclic
  • Pyrimidines
  • MTOR protein, human
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases
  • Atg7 protein, human
  • Autophagy-Related Protein 7
  • Ubiquitin-Activating Enzymes

Grant support

This work was supported by Mesothelioma Applied Research Foundation Grant 255458 to DB ( Additional funding was provided by the Simmons Mesothelioma Foundation—Simmons Fellowship in Mesothelioma Research to CF ( Further support was provided by the Swiss National Science Foundation and Baugarten Foundation grants to EFB. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.