Malignant pleural mesothelioma (MPM) is one of the deadliest and most heterogeneous tumors,
highly refractory to multimodal therapeutic approach, including surgery, chemo- and radiotherapy.
Preclinical and clinical studies exploring the efficacy of drugs targeting tyrosine kinases, angiogenesis
and histone deacetylases, did not fulfil the expected clinical benefits. Thus, novel molecular
targets should be identified from a definite knowledge of the unique biology and most relevant transduction
pathways of MPM cells. Cancer stem cells (CSCs) are a subset of malignant precursors responsible
for initiation, progression, resistance to cytotoxic drugs, recurrence and metastatic diffusion of tumor cells.
CSCs are putative driving factors for MPM development and contribute to its clinical and biological heterogeneity; hence,
targeted eradication of CSCs represents an ineludible goal to counteract MPM aggressiveness. In this context, innovative
preclinical models could be exploited to identify novel intracellular pathway inhibitors able to target CSC viability. Novel
drug targets have been identified among key factors responsible for the oncogenic transformation of mesothelial cells, often
directly induced by asbestos. These include mitogenic and anti-apoptotic signaling that may also be activated by
autocrine and paracrine cytokine pathways controlling cell plasticity. Both signaling pathways affecting proto-oncogene
and transcription factor expression, or genetic and epigenetic alterations, such as mutations in cell cycle genes and silencing
of tumor suppressor genes, represent promising disease-specific targets. In this review we describe current knowledge
of MPM cell biology, focusing on potential targets to be tested in pharmacological studies, and highlighting results and
challenges of clinical translation.