PP2A: A Promising Biomarker and Therapeutic Target in Endometrial Cancer

Abstract

Over the last decade, the use of targeted therapies has immensely increased in the treatment of cancer. However, treatment for endometrial carcinomas (ECs) has lagged behind, although potential molecular markers have been identified. This is particularly problematic for the type II ECs, since these aggressive tumors are usually not responsive toward the current standard therapies. Therefore, type II ECs are responsible for most EC-related deaths, indicating the need for new treatment options. Interestingly, molecular analyses of type II ECs have uncovered frequent genetic alterations (up to 40%) in PPP2R1A, encoding the Aα subunit of the tumor suppressive heterotrimeric protein phosphatase type 2A (PP2A). PPP2R1A mutations were also reported in type I ECs and other common gynecologic cancers, albeit at much lower frequencies (0-7%). Nevertheless, PP2A inactivation in the latter cancer types is common via other mechanisms, in particular by increased expression of Cancerous Inhibitor of PP2A (CIP2A) and PP2A Methylesterase-1 (PME-1) proteins. In this review, we discuss the therapeutic potential of direct and indirect PP2A targeting compounds, possibly in combination with other anti-cancer drugs, in EC. Furthermore, we investigate the potential of the PP2A status as a predictive and/or prognostic marker for type I and II ECs.

Keywords: CIP2A; PME-1; PP2A activating drug; PPP2R1A; endometrial cancer; phosphatase targeted therapy; serous endometrial carcinoma; type II endometrial carcinoma.

Figure 1

The structure of the protein phosphatase PP2A. Three subunits can be distinguished: the scaffolding A subunit (Aα/Aβ) composed of 15 heat repeats (HR), the catalytic C subunit (Cα/Cβ) and the 4 classes of regulatory B subunits. PPP2R1A hotspot mutations occur in HR 5 (p.P179R/L, p.R183G/P/Q/W) and HR 7 (p.S256F/Y), which are involved in B subunit binding. The many regulatory B subunits allow for PP2A to target a vast array of components of important signaling pathways often involved in tumorigenesis.

Figure 2

(A) PPP2R1A mutations across all available cBioportal cancer studies except ECs. The three hotspot mutations (p.P179; p.R183; and p.S256) are clearly depicted. Most tumors (66.3%) had mutations in p.R183 while only 22.5% and 11.3% had mutations in p.P179 and p.S256, respectively. (B) PPP2R1A missense mutations reported in type II ECs (cBioportal). In contrast with other cancers, PPP2R1A mutations mostly occur at residue p.P179 (56%), while only 20% had mutations in residue p.R183. Also more EC tumors (24%) had mutations in p.S256 compared to other cancer types. HR, HEAT-repeat.

Figure 3

The overall survival of patients with type II serous EC with (blue line) and without PPP2R1A mutations (red line). (n = 44), data were extracted from the UCEC-TCGA study available in the cBioportal database.