CD157: a predictive marker of response to tailored therapies in patients with malignant pleural mesothelioma

Malignant pleural mesothelioma (MPM) is a rare, aggressive tumor affecting the pleural cavity. Cisplatin (CDDP)-based therapy is the first-line treatment, but its efficacy is often limited by intrinsic or acquired resistance. CD157 is a glycoprotein expressed in 85% of MPM, where high expression correlates with worst outcome, dysregulation of PI3K/Akt/mTOR pathway and reduced sensitivity to platinum-based treatments. In this study we explored the ability of NVP-BEZ235 (a PI3K/mTOR double inhibitor) to improve cisplatin-sensitivity using in vitro MPM cell lines engineered for the expression of CD157. The results showed that in CD157-positive MPM cells, NVP-BEZ235 i) reduced cell proliferation and, ii) when combined to CDDP, abrogated the CDDP-mediated cell cycle arrest in G2/M phase thus restoring apoptosis. Conversely, no appreciable effects were observed in MPM without CD157, which are cisplatin-sensitive. In addition, we demonstrated that CD157-positive MPM show higher basal autophagy compared to CD157-negative MPM. Autophagy takes part to the regulation of CDDP-resistance. Indeed, chloroquine, a pharmacological autophagy inhibitor, suppressed proliferation of the CD157-positive, CDDP-resistant, but not those of CD157-negative MPM cells. Moreover, addition of chloroquine to CDDP significantly increased the efficacy of cisplatin in CD157-positive but not in CD157-negative cells. In conclusion, the reduced sensitivity to CDDP in CD157-positive MPM relies on deregulation of the PI3K/Akt/mTOR pathway leading to impaired apoptosis, and by increased protective autophagy. These results prompt speculation that CD157 may be a predictive marker of response for patients with highly aggressive MPM, who might benefit from combined therapy with CDDP and specific inhibitors targeting PI3K/mTOR or autophagy.