Protein Phosphatase 2A dysfunctions in malignant pleural mesothelioma: oncogenic mechanisms and therapeutic opportunities

Malignant pleural mesothelioma (MPM) is a rare cancer of the pleural surfaces, frequently related to asbestos exposure. It is characterized by a grim prognosis (5-year-survival: <5%), underscoring the need for improved therapies. Here, we propose the implementation of targeted therapies in a molecularly well-defined subgroup of MPM, characterized by specific dysfunctions of a tumor suppressive phosphatase, PP2A, to improve therapeutic outcome. PP2A dysfunction occurs in 10-46% of MPM, correlating with decreased overall survival. We will model these clinically relevant PP2A dysfunctions into human MPM cell lines (WP1), and subsequently, determine their impact on the oncogenic and biochemical phenotype of the cells (WP2), and on the response to targeted therapeutics, including pharmacologic PP2A activators and kinase inhibitors (WP3). Like this, we will provide the first fundamental insights into the role of PP2A in MPM biology, and establish PP2A dysfunctions as a stratification marker for identification of novel therapeutic vulnerabilities.