PP2A targeting: balancing anticancer potential and neurological risk.
4 affiliations
- 1Advitam Laboratory, Belgrade, Serbia.
- 2Institute of Cytology RAS, St. Petersburg, Russia.
- 3The Laboratory of Bio- and Chemoinformatics, School of Computer Science, Physics and Technology, HSE University, St. Petersburg, Russia.
- 4Department of Neurobiology, Institute for Biological Research "Siniša Stanković" - National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia.
Abstract
Protein phosphatase 2A (PP2A) is a multifunctional serine/threonine phosphatase that regulates cell-cycle progression, oncogenic signaling, neuronal development, synaptic homeostasis, and protein proteostasis. Its dysregulation contributes to cancer, whereas impaired PP2A activity in the nervous system is linked to neurodevelopmental disorders and neurodegenerative proteinopathies, including tau and α-synuclein pathology. These divergent roles create both opportunities and safety challenges for PP2A-directed therapies. This review examines PP2A as a modular holoenzyme system whose subunit composition determines substrate specificity and context-dependent biological effects. We discuss PP2A dysfunction in cancer, including genetic and regulatory alterations affecting PP2A subunits, assembly, and endogenous inhibitors, and compare therapeutic PP2A activation with transient inhibition. The latter approach is exemplified by LB100, which sensitizes treatment-stressed tumor cells to chemotherapy, radiotherapy, or immunotherapy by disrupting checkpoint adaptation and stress recovery. We further evaluate the neurological implications of systemic phosphatase inhibition, LB100 conversion to the active metabolite endothall, clinical safety and pharmacokinetic data, and the limited brain-tumor penetration of intact LB100. We propose that the clinical utility of PP2A inhibition depends on defining a therapeutic corridor that integrates dosing schedule, parent-drug and metabolite exposure, tumor target engagement, biomarker-informed patient selection, and preservation of PP2A-dependent homeostasis in normal tissues, particularly the nervous system.
Related
- Poison exon splicing in the human brain provides a new paradigm for understanding and targeting neurological disorders
- Targeting the ERK2 D-Recruitment Site with Anticancer Peptides from the DRAMP Database: An Integrated In Silico Study
- Inhibitory, Anticancer Efficacy and Structural Insights of a Novel Ethyl 1-Hydroxy-3-Oxo-1-Phenylisoindoline-2-Sulfonate Compound Selectively Targeting Human CA IX and CA XII Carbonic Anhydrase, Ferroptosis-Mediated Cell Death.
- Combining Ligand- and Structure-Based Approaches to Develop Haloacetamide-Derived Di(hetero)arylmethanes as Potential Anticancer Agents
- Phytochemical Profiling and Anticancer Potential of Ipomoea hederifolia L. Root Extract: LC-MS Characterization and Molecular Docking Insights.
BibTeX
@article{chigriai2026pp2a,
title = {{PP2A targeting: balancing anticancer potential and neurological risk.}},
author = {Margarita Chigriai and Nina Kraskovskaya and Anastasia Bolshakova and Natalia O Porozova and Yuri B Porozov and Milica Pešić},
journal = {Frontiers in cell and developmental biology},
year = {2026},
month = oct,
doi = {10.3389/fcell.2026.1945801},
url = {https://europepmc.org/article/MED/42947971},
note = {CC BY},
}
RIS
TY - JOUR
TI - PP2A targeting: balancing anticancer potential and neurological risk.
AU - Margarita Chigriai
AU - Nina Kraskovskaya
AU - Anastasia Bolshakova
AU - Natalia O Porozova
AU - Yuri B Porozov
AU - Milica Pešić
PY - 2026
DA - 2026/10/13
JO - Frontiers in cell and developmental biology
DO - 10.3389/fcell.2026.1945801
UR - https://europepmc.org/article/MED/42947971
AB - Protein phosphatase 2A (PP2A) is a multifunctional serine/threonine phosphatase that regulates cell-cycle progression, oncogenic signaling, neuronal development, synaptic homeostasis, and protein proteostasis. Its dysregulation contributes to cancer, whereas impaired PP2A activity in the nervous system is linked to neurodevelopmental disorders and neurodegenerative proteinopathies, including tau and α-synuclein pathology. These divergent roles create both opportunities and safety challenges for PP2A-directed therapies. This review examines PP2A as a modular holoenzyme system whose subunit composition determines substrate specificity and context-dependent biological effects. We discuss PP2A dysfunction in cancer, including genetic and regulatory alterations affecting PP2A subunits, assembly, and endogenous inhibitors, and compare therapeutic PP2A activation with transient inhibition. The latter approach is exemplified by LB100, which sensitizes treatment-stressed tumor cells to chemotherapy, radiotherapy, or immunotherapy by disrupting checkpoint adaptation and stress recovery. We further evaluate the neurological implications of systemic phosphatase inhibition, LB100 conversion to the active metabolite endothall, clinical safety and pharmacokinetic data, and the limited brain-tumor penetration of intact LB100. We propose that the clinical utility of PP2A inhibition depends on defining a therapeutic corridor that integrates dosing schedule, parent-drug and metabolite exposure, tumor target engagement, biomarker-informed patient selection, and preservation of PP2A-dependent homeostasis in normal tissues, particularly the nervous system.
SN - 2296-634X
ER -