Biomolecular Pathways and Malignant Pleural Mesothelioma

Although asbestos is banned in several countries, malignant pleural mesothelioma (MPM) incidence is increasing worldwide, and this cancer remains a disease of concern. MPM is a very severe cancer, with no curative treatment despite the development of different kinds of therapeutic approaches. To date the treatments are based on multimodal chemotherapy and surgery. The longest survival data in patients is obtained with the combination of chemotherapy, radical surgery and radiotherapy. The development of targeted therapies offers new strategies to kill cancer cells. To be efficient, they need a precise identification of the critical targets. This objective can be reached by a deep knowledge of the molecular and physiological changes associated with the neoplastic transformation of MPM cells. One approach consists in the identification of gene mutations, epigenetic alterations, study of gene expression profiles and identification of the deregulated signalling pathways in malignant cells, with the goal to select molecules or mechanisms that could kill cancer cells or abolish tumour growth. The present knowledge on the main alterations in genes and signalling pathways indicates that MPM have recurrent mutations in a limited number of tumour suppressor genes, and oncogenic mutation in the promoter of TERT. A number of studies have emphasized the role of receptor tyrosine kinase (RTK) driven signalling, although not related to mutations in RTK. Multiple signalling pathways are altered in MPM. Transcriptomic analyses permitted to classify mesotheliomas in subgroups, according to prognosis. They showed heterogeneity of MPM, not only defined by the histological subtype, but also by molecular features. So far, targeted therapy was unsuccessful, at least partly due to the heterogeneity of MPM. Moreover, the complexity stands in the interconnection between pathways, which is a challenge to choose the most critical target for an efficient therapy. This review summarizes the main alterations identified in genes and signalling pathways in MPM, the impact on therapeutics, and discusses the future of these approaches to improve MPM outcome, especially knowing molecular and physiological characteristics of MPM to define their diversity.

Keywords: Receptor tyrosine kinase, signalling pathways, targeted therapy, transcriptomic analysis.