The combination of sorafenib and everolimus shows antitumor activity in preclinical models of malignant pleural mesothelioma

Abstract

BackgroundMalignant Pleural Mesothelioma (MPM) is an aggressive tumor arising from mesothelial cells lining the pleural cavities characterized by resistance to standard therapies. Most of the molecular steps responsible for pleural transformation remain unclear; however, several growth factor signaling cascades are known to be altered during MPM onset and progression. Transducers of these pathways, such as PIK3CA-mTOR-AKT, MAPK, and ezrin/radixin/moesin (ERM) could therefore be exploited as possible targets for pharmacological intervention. This study aimed to identify ‘druggable’ pathways in MPM and to formulate a targeted approach based on the use of commercially available molecules, such as the multikinase inhibitor sorafenib and the mTOR inhibitor everolimus.MethodsWe planned a triple approach based on: i) analysis of immunophenotypes and mutational profiles in a cohort of thoracoscopic MPM samples, ii) in vitro pharmacological assays, ii) in vivo therapeutic approaches on MPM xenografts. No mutations were found in ‘hot spot’ regions of the mTOR upstream genes (e.g. EGFR, KRAS and PIK3CA).ResultsPhosphorylated mTOR and ERM were specifically overexpressed in the analyzed MPM samples. Sorafenib and everolimus combination was effective in mTOR and ERM blockade; exerted synergistic effects on the inhibition of MPM cell proliferation; triggered ROS production and consequent AMPK-p38 mediated-apoptosis. The antitumor activity was displayed when orally administered to MPM-bearing NOD/SCID mice.ConclusionsERM and mTOR pathways are activated in MPM and ‘druggable’ by a combination of sorafenib and everolimus. Combination therapy is a promising therapeutic strategy against MPM.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1363-1) contains supplementary material, which is available to authorized users.

Novel systemic therapy against malignant pleural mesothelioma

“…While these findings are comparable to other small molecular inhibitors of angiogenesis, additional studies are needed to determine if this translates into clinical benefit. As discussed below, pre-clinical studies demonstrate efficacy of sorafenib combined with everolimus in mesothelioma xenografts (85), which provides a rationale for combination studies with multiple agents.…”

“…Unfortunately, patients with MPM who had progressed after first line therapy did not respond to everolimus in a phase II study (114). Preclinical models have demonstrated promising efficacy in MPM patient derived xenograft models with a combination of everolimus and sorafenib (85) suggesting that the combination of receptor tyrosine kinase and mTOR inhibition could be effective. Other inhibitors of PI3K/mTOR are currently in clinical trials.…”

Modulation of Autophagy by Sorafenib: Effects on Treatment Response

“…Sorafenib activates AMPK being this effect potentially relevant during induction of autophagy in cancer cells (Figure 1 ; Eum et al, 2013 ; Fischer et al, 2014 ; Tesori et al, 2015 ). Sorafenib is able to induce AMPK phosphorylation in a time-dependent fashion and in a dose-dependent manner in experimental models in vitro , specifically in cultured cells coming from different types of human tumors (Eum et al, 2013 ; Fumarola et al, 2013 ; Pignochino et al, 2013 , 2015 ; Fischer et al, 2014 ; Groenendijk et al, 2015 ; Tesori et al, 2015 ). It has been demonstrated that the incubation with 5 μM of sorafenib in multidrug resistant cells cultured in vitro can stimulate AMPK phosphorylation in a time-dependent manner, starting at 0.5 h after treatment (Eum et al, 2013 ).…”

The Genetic Landscape of Malignant Pleural Mesothelioma: Results from Massively Parallel Sequencing

“…Moreover, combining PI3K/AKT pathway inhibitors with inhibitors of other pathways (e.g., selumetinib or sorafenib) might improve efficacy. 65,66 In addition to the alterations in genes belonging to these four pathways (see Fig. 3), alterations in some other genes were reported (see Table 2).…”