Abstract
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.
Highlights
Malignant pleural mesothelioma is a recalcitrant solid tumor of the pleural lining for which, to date, no curative therapy is available
To investigate if sensitivity to GDC-0980 is a feature of a subset of mesotheliomas, we studied 4 more mesothelioma cell lines (SARC, VAMT, JMN and MSTO-211H)
Using tumor fragment spheroids derived from patient tumors, we confirmed our findings from the cell lines, showing that the response to GDC-0980 correlates with the presence of ATG13 puncta. By using these 3D models, we have found that there is a group of tumors with autophagy that is sensitive to PI3K/mTOR inhibition with GDC-0980
Summary
Malignant pleural mesothelioma is a recalcitrant solid tumor of the pleural lining for which, to date, no curative therapy is available. We have proposed a role for the PI3K/Akt/mTOR pathway in 3D multicellular resistance [1, 2]. Activation of the Akt/mTOR pathway is detected in the majority of mesothelioma cell lines [9] and, in mouse models of mesothelioma, its inhibition has been shown to improve response to chemotherapy [10,11,12]. We have previously tested several inhibitors of the PI3K/Akt (LY294002 and wortmannin) and mTOR (rapamycin) pathways or both (PI-103)[14], by using 3D mesothelioma models grown from cell lines (multicellular spheroids) and actual tumor (tumor fragment spheroids) [1, 2]. Our work has shown that the activity of the inhibitors was evident only in a 3D setting, where we could identify an important role for the mTOR pathway. With the recent development of dual inhibitors, we wanted to investigate the therapeutic advances of these new compounds by testing them in our 3D models
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
