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Int. J. Mol. Sci. 2018, 19(8), 2380; https://doi.org/10.3390/ijms19082380

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

1
Laboratory of Protein Phosphorylation & Proteomics, Department of Cellular & Molecular Medicine, University of Leuven (KU Leuven), B-3000 Leuven, Belgium
2
Leuven Cancer Institute (LKI), B-3000 Leuven, Belgium
*
Author to whom correspondence should be addressed.
Received: 29 June 2018 / Revised: 2 August 2018 / Accepted: 8 August 2018 / Published: 13 August 2018
(This article belongs to the Special Issue Molecular Research of Endometrial Pathophysiology)
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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. View Full-Text
Keywords: endometrial cancer; type II endometrial carcinoma; targeted therapy; kinase inhibitor; molecular marker; protein kinase; protein phosphatase; PP2A; PPP2R1A; SMAP endometrial cancer; type II endometrial carcinoma; targeted therapy; kinase inhibitor; molecular marker; protein kinase; protein phosphatase; PP2A; PPP2R1A; SMAP
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Remmerie, M.; Janssens, V. Targeted Therapies in Type II Endometrial Cancers: Too Little, but Not Too Late. Int. J. Mol. Sci. 2018, 19, 2380.

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