Targeting PP2A in cancer: Combination therapies

Abstract

The serine/threonine phosphatase PP2A regulates a vast portion of the phosphoproteome including pathways involved in apoptosis, proliferation and DNA damage response and PP2A inactivation is a vital step in malignant transformation. Many groups have explored the therapeutic venue of combining PP2A reactivation with kinase inhibition to counteract the very changes in tumor suppressors and oncogenes that lead to cancer development. Conversely, inhibition of PP2A to complement chemotherapy and radiation-induced cancer cell death is also an area of active investigation. Here we review the studies that utilize PP2A targeted agents as combination therapy in cancer. A potential role for PP2A in tumor immunity is also highlighted.

Keywords: Cell signaling; Protein phosphatases; Targeted therapies.

Figure 1.

Protein Phosphatase 2A (PP2A) is a heterotrimeric enzyme complex composed of an ‘A’ scaffolding subunit, a ‘B’ regulatory subunit, and a ‘C’ catalytic subunit. Multiple isoforms exist for each. B-subunits demonstrate the greatest diversity with 16 identified isoforms grouped into 4 families. During PP2A biogenesis, monomeric C-subunit interaction with PTPA induces conformational and biochemical changes that activate the C-subunit prior to A-subunit binding and dimer formation. Methylation of the C-subunit at the carboxyl terminus by LCMT then takes place to facilitate binding of specific methyl-sensitive B-subunits. Demethylation carried out by PME-1 may conversely alter or reduce holoenzyme assembly. Endogenous inhibitors of PP2A such as TIPRL, SET, and CIP2A may further regulate PP2A physiologic activity.

Figure 2.

Simplified signaling pathways downstream of growth factor signaling. PP2A negatively regulates proliferation and cell survival at multiple nodes. However, PP2A may be inhibited in cells with aberrantly active growth signaling resulting from activating mutations or oncogenic fusion proteins of the receptor tyrosine kinases shown, thereby allowing increased signaling through these pathways and tumorigenic progression. In this setting, simultaneously inhibition of oncogenic kinases and reactivation of PP2A harbors the potential for synergistic antineoplastic effects.

Figure 3.

PP2A exerts regulatory activity against multiple substrates within the DNA damage response (DDR) pathways. Shown is a simplified schematic of reported PP2A targets; a complete picture of PP2A’s role would involve added timing and contextual dynamics. Critically, PP2A activity against ATM and Chk1 / Chk2 promotes the high-integrity homologous recombination (HR) repair of damaged DNA and resolution of γH2AX foci marking sites of DNA strand break. In parallel, cell cycle progression is halted due to PP2A inhibition of MDM2 / activation of p53, as well as PP2A activity against PLK1, Aurora Kinase A (AurA), Wee1, and cdc25 that altogether inhibits CDK1/CyclinB. (A) In the face of significant DNA damage induced by radiation or a chemotherapeutic compound, PP2A inhibition impairs damage response and repair, and appropriate cell cycle arrest. Damage persists and cells that attempt to divide experience mitotic catastrophe due to a lethal loss of genome integrity. (B) Similar to BRCA1/2, PP2A has multiple key roles in facilitating HR repair that may allow it to be a candidate for synthetic lethality when its inactivation is coupled with PARP inhibition.

Figure 4.

The complex roles of PP2A in immune checkpoint signaling. PP2A activation may increase tumor immunity via dephosphorylation and subsequent degradation of MYC as well as inhibition of MAPK and PI3K pathways. In contrast, loss of PP2A is linked to reduced Treg function, and specific depletion of the regulatory subunit B55δ was shown to increase tumor immunity.