Protein Phosphatase 2A Modulation Selectively Targets Cancer Cells by Activating Non-Canonical Pathways that Regulate Cell Fate in Response to Cellular Stress
Creators: name: A Avelar, Rita
Publisher: name: My University
Year: 2023
Subjects: subject: Protein Phosphatase 2A
subject: High-Grade Serous Cancer
subject: Ovarian Cancer
subject: Cellular Stress
subject: Small Molecule Modulator
subject: Apoptotic Cell Death
subject: Pathology
subject: Health Sciences

description: High-grade serous cancer (HGSC) is the most lethal gynecological malignancy and accounts for ~70% of all ovarian tumors. Recent findings have enhanced our understanding of the genetic alterations that drive HGSC oncogenesis, significantly contributing to the clinical management of HGSC and guiding patient stratification. However, HGSC mortality rates have remained stagnant over the past three decades, with a 5-year survival rate below 30%. Genetically, over 50% of HGSCs are characterized by a high degree of genomic instability caused by homologous recombination defects (HRD), rendering PARP inhibitors (PARPis) the mainstay of HGSC-targeted therapeutic approaches. As HGSC tumors are unable to use HR pathways to repair double-strand breaks, they ultimately rely on single-strand break repair to resolve DNA insults, a mechanism highly exploited by PARPis. However, despite most patients initially responding favorably to these treatments, ~80% eventually relapse with incurable and more aggressive resistant disease. Thus, there is an urgent need for novel therapies to be tailored toward the treatment of HGSC. Herein, we uncovered that the tumor suppressor PP2A, a master regulator of serine/ threonine phosphatase activity, is frequently lost in HGSC, second only to TP53 alterations. 95% of HGSC tumors exploit PP2A inactivation via the loss-of-heterozygosity (LOH), rendering this haploinsufficient phosphatase unable to functionally inhibit oncogenic traits essential for HGSC tumorigenesis. Given this discovery, we postulated that modulating PP2A’s activity, by stabilizing tumor-suppressive PP2A heterotrimers that counteract malignant traits underlying HGSC oncogenesis, can hold tremendous therapeutic potential in HGSC models. To test this hypothesis, we utilized a tool compound modulator of PP2A activity known as a small-molecule activator of PP2A (SMAP). Our studies revealed that SMAP stabilizes and regulates the remnant copy of PP2A-Aα available, biasing the B-subunit pools to drive tumor-suppressive functions, alone or in combination with PARPi. We also uncovered that SMAP induces robust apoptotic cell death in established and primary HGSC cell lines as well as in numerous genetically distinct HGSC PDX mouse models via synthetic lethality. SMAP molecules produce potent anticancer properties, abrogating tumor growth in various human malignancies with efficacy linked to the dephosphorylation and degradation of numerous oncogenic substrates that drive disease. Intriguingly, SMAP is highly tolerable in animal systems, yet the molecular mechanism behind SMAP’s lack of overt cytotoxic effects in normal tissues remained unclear. This prompted us to investigate the effects of PP2A modulators in non-transformed fallopian tube (FT) human models to further understand the mechanism by which these molecules trigger different responses depending on the cellular context, remaining tolerable in non-transformed cells but toxic to cancer. Combined, our studies revealed that ISR signaling is upregulated with SMAP, showing differential responses and translational signatures in cancer versus non-transformed models. Interestingly, under the same SMAP stimulus, these cell lines activate different downstream response mechanisms, yielding two distinct fates. In cancer cells, SMAP exposure drives specific t-RNA charging signaling pathways to bias the translational machinery toward activating oxidative stress and UPR genes, ultimately leading to the increase of death signals such as autophagy, necroptosis, and apoptosis. Oppositely, FTs prioritize restoring translational and secretory abilities, by shutting down all pro-death signaling pathways activated in the cancer lines treated with SMAP. Collectively, our studies reveal a new role of PP2A in regulating ISR via ATF4 modulation, activating distinct cooperative mechanisms that ultimately dictate cell fate, yielding different outcomes in malignant and non-tumorigenic cellular models.