JPM, Vol. 12, Pages 1993: AXL and MET Tyrosine Kinase Receptors Co-Expression as a Potential Therapeutic Target in Malignant Pleural Mesothelioma

Malignant pleural mesothelioma (MPM) is a highly aggressive and rare tumor arising from the pleura [1]. MPM is difficult to treat and commonly associated with asbestos exposure, which is its main risk factor [2]. MPM incidence is increasing worldwide, and a peak is expected in the coming decades. However, the exact time of this peak will vary among countries, owing to differences in the timing of the reduction in or the prohibition of asbestos use [3]. Histologically, three main MPM subtypes are distinguished: the epithelioid, the sarcomatoid and the biphasic, with the latter combining features of the other two histotypes [4]. The epithelioid is the most common (60% or more) histological subtype and the less aggressive; the sarcomatoid is the rarest subtype (5,6]. The long-term survival rate of MPM is poor, ranging approximately from 14 to 15 months despite the treatment. Therapeutic options include multi-modality approach based on chemotherapy, surgical resection, and thoracic radiation, lacking any personalized treatment strategies [7]. In recent years, extensive research has focused on the identification of prognostic and predictive markers, however, distinct from other cancers, no target therapies have been currently approved for MPM. The genetic landscape of MPM is characterized by several genetic alterations including the deregulated activation of several signaling pathways, particularly the canonical receptor tyrosine kinase pathways [8,9]. Hmeljak et al. proposed a new integrated molecular classification of MPM, showing for the first-time subgroups of MPM from a biological point of view [10]. Among all the proposed targets emerged, the activation of various receptor tyrosine kinases (RTKs) plays a central role in MPM pathogenesis, leading to the oncogenic progression of non-neoplastic mesothelial progenitor to malignant cells. In vitro studies showed that drugs targeting RTKs might be candidate inhibitors in the treatment of MPM based on the activation of several kinase signaling pathways in this cancer [11]. Despite the proven RTK activation in mesothelioma and encouraging in vitro results with RTK inhibitors, clinical trials have shown no relevant clinical activity of any single targeted tyrosine kinase inhibitor (TKIs) in MPM patients [12]. The limited clinical success of a single agent could be justified by the co-activation of multiple RTKs resulting in mesothelioma cell proliferation and survival. Several studies demonstrated the activation of multiple RTKs in MPM, including EGFR, MET, PDGFRA, PDGFRB, and IGF1R [11]. MET is a RTK involved in cell growth, replication, and motility, that could play a role in tumorigenesis of several human cancers through multiple mechanisms, including altered regulation, genetic mutations, and upregulation of its ligand hepatocyte growth factor (HGF) [13]. MET overexpression has been reported in approximately 74–100% of MPMs, although the molecular mechanisms of its upregulation remain incompletely understood [14,15]. MET gene mutations have been identified in 3–16% of MPMs, resulting in a variable clinical value [11,14]. MET amplification in parallel with MET over-expression has been described in non-small cell lung cancer and gastrointestinal tumors, while it represents a rare event in MPM with a frequency less than 1% [16]. Previous in vitro studies showed the efficacy of MET inhibition by small molecule inhibitor or RNAi knockdown in MPM cell lines, resulting in the decreased phosphorylation of MET and the cell cycle arrest [12]. AXL is a member of the TAM RTK subfamily, implicated in cell survival, epithelial-to-mesenchymal transition, and drug resistance. AXL can be activated through different mechanisms, including ligand-independent dimerization and ligand-dependent dimerization especially driven by Gas-6 its major ligand. AXL overexpression has been associated with adverse prognosis in several neoplasms such as hepatocellular carcinoma, esophageal carcinoma, pancreatic carcinoma, thyroid carcinoma, and colon carcinoma [17]. Pinato et al. have validated AXL overexpression in a large series of MPM confirming an independent prognostic value of the receptor expression. Moreover, the prognostic power of AXL expression could be stronger than that of commonly used prognostic factors including tumor stage and EORTC prognostic score [18]. In vitro studies have previously documented that AXL inhibition can suppress the proliferation and the invasion of mesothelioma cells suggesting its potential role as therapeutic target in MPM [12,18]. The main aim of the present study was to investigate the potential role of AXL and MET receptors in MPM. First, we analyzed AXL and MET overexpression in a wide series of MPM patients through immunohistochemical analyses, and moreover the amplification of both two genes was investigated by FISH. Then, a second objective was to assess in vitro efficacy of treatment with AXL and MET multitargets inhibitors, to evaluate putative correlations between the target’s expression and the cell’s drug sensitivity.

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