Targeted Therapies in Type II Endometrial Cancers: Too Little, but Not Too Late

Abstract

Type II endometrial carcinomas (ECs) are responsible for most endometrial cancer-related deaths due to their aggressive nature, late stage detection and high tolerance for standard therapies. However, there are no targeted therapies for type II ECs, and they are still treated the same way as the clinically indolent and easily treatable type I ECs. Therefore, type II ECs are in need of new treatment options. More recently, molecular analysis of endometrial cancer revealed phosphorylation-dependent oncogenic signalling in the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways to be most frequently altered in type II ECs. Consequently, clinical trials tested pharmacologic kinase inhibitors targeting these pathways, although mostly with rather disappointing results. In this review, we highlight the most common genetic alterations in type II ECs. Additionally, we reason why most clinical trials for ECs using targeted kinase inhibitors had unsatisfying results and what should be changed in future clinical trial setups. Furthermore, we argue that, besides kinases, phosphatases should no longer be ignored in clinical trials, particularly in type II ECs, where the tumour suppressive phosphatase protein phosphatase type 2A (PP2A) is frequently mutated. Lastly, we discuss the therapeutic potential of targeting PP2A for (re)activation, possibly in combination with pharmacologic kinase inhibitors.

Keywords: PP2A; PPP2R1A; SMAP; endometrial cancer; kinase inhibitor; molecular marker; protein kinase; protein phosphatase; targeted therapy; type II endometrial carcinoma.

Figure 1

Schematic overview of the PI3K and MAPK pathways and important substrates. Black arrows represent activation. Red lines represent endogenous inhibition through feedback/cross-talk. Dotted red lines represent inhibition with pharmacologic kinase inhibitors. The heterotrimeric PP2A complex is represented in red (A subunit), blue (B subunit) and green (C subunit). Both pathways can be targeted at several levels using pharmacologic kinase inhibitors. However, single agent inhibitors targeting mTORC1 (e.g., everolimus) will deactivate the negative feedback loops from p70S6K to mTORC2 and PI3K. The use of a dual PI3K/mTOR inhibitor could circumvent this problem. There is also cross-talk between the PI3K and MAPK pathway, which could be evaded by using the combination of a PI3K and MAPK (e.g., MEK inhibitor) pathway inhibitor. Anti-RTKs (e.g., Trastuzumab) target the extracellular domain of the RTKs. TK inhibitors (e.g., Lapatinib) target the intracellular tyrosine kinase activity of the RTKs. Furthermore, PP2A acts as a tumour suppressor on many components of both pathways and should therefore be considered when targeting kinases. Additionally, it is an attractive target for activation, and hence PI3K and MAPK pathway downregulation, potentially in combination with kinase inhibitors. The PI3K and MAPK pathways have several substrates in common (GSK-3β, FOXO, Bad and c-Myc), which are involved in cell proliferation and cell survival. Some substrates, like FOXO and GSK-3β, are activated by Akt, independently of mTORC1. 4EBP1: eukaryotic translation initiation factor 4E-binding protein 1, Bad: Bcl-2-associated death promoter, FOXO: forkhead box protein, GSK-3β: glycogen synthase kinase 3β, IRS-1: insulin receptor substrate 1, mTOR: mammalian target of rapamycin, PI3K: phosphatidyl-4,5-bisphosphate 3-kinase, PP2A: protein phosphatase 2A, RTK: receptor tyrosine kinase, S6: ribosomal protein S6, TK: tyrosine kinase, MAPK: mitogen-activated protein kinase; ERK: extracellular signal-regulated kinase; MEK: mitogen-activated protein kinase kinase.

Figure 2

The heterotrimeric PP2A complex with activating and inactivating mechanisms. Heat repeat (HR) 5 and 7 are represented with their intra-repeat loops in subunit A. These intra-repeat loops harbour the most recurrent PPP2R1A hotspot mutations identified in type II ECs. Endogenous inhibition of PP2A can occur via SET, CIP2A and PME-1, which act on the C subunit. TPDYFL is the conserved motif in the C-terminal tail of the catalytic C subunit. Phosphorylation of the tyrosine (Y) is thought to cause inactivation, while methylation of the carboxyterminal leucine (L) of the C subunit promotes binding of specific B subunits, and thereby assembly of active trimers. PME-1 demethylates this leucine, and stabilises inactive PP2A complexes. PTPA is necessary for endogenous activation of inactive PP2A complexes. SMAP is a small molecule activator of PP2A, which binds at heat repeat 5 in close proximity to the hotspot mutations in PPP2R1A. The vast array of regulatory B subunits allows for the targeting of PP2A to many different substrates. A: Scaffolding A subunit; B, B′, B″, B′′′: The four families of regulatory B subunits, each containing several isoforms; C: catalytic C subunit; CH₃: methyl group; CIP2A: cancerous inhibitor of PP2A; HR: heat repeat; P: phosphate group (PO₄³⁻); PME-1: PP2A methylesterase 1; PTPA: phosphatase 2A phosphatase activator; SET: Suvar/Enhancer of zeste/Trithorax; SMAP: small molecule activator of PP2A.