Abstract
Malignant mesothelioma (MM) is a deadly tumor mainly caused by exposure to asbestos. Unfortunately, no current treatment is able to change significantly the natural history of the disease, which has a poor prognosis in the majority of patients. The non-receptor tyrosine kinase SRC and other SRC family kinase (SFK) members are frequently hyperactivated in many cancer types, including MM. Several works have indeed suggested that SFKs underlie MM cell proliferation, survival, motility, and invasion, overall affecting multiple oncogenic pathways. Consistently, SFK inhibitors effectively counteracted MM cancerous features at the preclinical level. Dasatinib, a multi-kinase inhibitor targeting SFKs, was also assessed in clinical trials either as second-line treatment for patients with unresectable MM or, more recently, as a neoadjuvant agent in patients with resectable MM. Here, we provide an overview of the molecular mechanisms implicating SFKs in MM progression and discuss possible strategies for a more successful clinical application of SFK inhibitors. Our aim is to stimulate discussion and further consideration of these agents in better designed preclinical and clinical studies to make the most of another class of powerful antitumoral drugs, which too often are lost in translation when applied to MM.
Highlights
Malignant mesothelioma (MM) is a very aggressive cancer of the serous membranes lining the body cavities: approximately 70–80% of MMs develop in the pleura, 20% in the peritoneum, and a minority affects the pericardium and tunica vaginalis [1]
This study showed that activation of the G protein-coupled purinergic receptor P2Y1 by SRC is involved in mediating MM cell migration and invasion induced by high cell surface levels of CD26/dipeptidyl peptidase 4 (DPP4) [46], a transmembrane glycoprotein, which has been suggested as a potential therapeutic target against MM [96]
CD26 was found to induce the nuclear translocation of the transcription factor TWIST1 via SRC activation (Figure 2); this resulted in enhanced expression and secretion of periostin [46], a matricellular protein involved in the promotion of cell migration and invasion [97], the low expression of which has been suggested as a prognostic factor for longer overall survival of MM patients [98]
Summary
Malignant mesothelioma (MM) is a very aggressive cancer of the serous membranes lining the body cavities: approximately 70–80% of MMs develop in the pleura, 20% in the peritoneum, and a minority affects the pericardium and tunica vaginalis [1]. The homozygous deletion of the CDKN2A locus causes functional inactivation of both p53 and RB1 tumor suppressor pathways [16]. This genomic deletion frequently involves an adjacent metabolic gene (methylthioadenosine phosphorylase, MTAP), generating a targetable vulnerability, which can be exploited therapeutically against. Oncogenic activating mutations in crucial regulators of growth and survival signaling, such as receptor tyrosine kinases (RTKs), rarely occur in MM, these kinases and downstream pathways are frequently overexpressed and hyperactivated in this cancer [11,13,14,24]. Many small molecules inhibiting SFKs and multiple other kinases (hereafter called “SFK inhibitors”, for simplicity) have been developed [33,34,35,36,37,38,39,40,41,42,43,44], some of which have been used in MM preclinical [45,46,47,48,49] and clinical studies [50,51] (Table 1)
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