Autophagy Correlates with the Therapeutic Responsiveness of Malignant Pleural Mesothelioma in 3D Models.
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.
Division of Pulmonary and Critical Care Medicine, Department of Medicine, San Francisco General Hospital, University of California San Francisco, San Francisco, California, 94110, United States of America.
Dario
D
Barbone
Division of Pulmonary and Critical Care Medicine, Department of Medicine, San Francisco General Hospital, University of California San Francisco, San Francisco, California, 94110, United States of America.
Carlo
C
Follo
Clinic of Oncology, University Hospital Zurich, 8044 Zurich, Switzerland.
Nohemy
N
Echeverry
Division of Nuclear Medicine & Molecular Imaging, Department of Radiology, Brigham & Women's Hospital and Harvard Medical School, Boston, Massachusetts, 02115, United States of America.
Victor H
VH
Gerbaudo
Department of Research Oncology, King's College London, London, United Kingdom.
Astero
A
Klabatsa
Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, 02115, United States of America.
Raphael
R
Bueno
Clinic of Oncology, University Hospital Zurich, 8044 Zurich, Switzerland.
Emanuela
E
Felley-Bosco
Division of Pulmonary and Critical Care Medicine, Department of Medicine, San Francisco General Hospital, University of California San Francisco, San Francisco, California, 94110, United States of America.
V Courtney
VC
Broaddus
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects*; D000071193:Autophagy-Related Protein 7; D000071183:Autophagy-Related Proteins; D015415:Biomarkers / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008654:Mesothelioma / Q000188:drug therapy* / Q000378:metabolism; D000086002:Mesothelioma, Malignant; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D018874:Spheroids, Cellular / Q000187:drug effects / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D044764:Ubiquitin-Activating Enzymes / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D000071193:Autophagy-Related Protein 7; D000071183:Autophagy-Related Proteins; D015415:Biomarkers; D019086:Bridged Bicyclo Compounds, Heterocyclic; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D011743:Pyrimidines; D058570:TOR Serine-Threonine Kinases; D044764:Ubiquitin-Activating Enzymes; C569670:1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno(3,2-d)pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one; C534291:ATG13 protein, human; C546842:MTOR protein, human; C509349:ATG7 protein, human