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.