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.
Highlights
Cancer is responsible for 1 in 6 deaths worldwide, and is thereby the second leading cause of mortality [1]
Recent advances in the understanding of the molecular mechanisms of gynaecological cancers and the discovery of potential molecular markers through large-scale genomics studies have paved the way to implementing targeted therapeutics, an approach already successfully used in other cancers
The Cancer Genome Atlas (TCGA) objectively classified endometrial tumours based on their molecular profiles, revealing four major genomic groups: Polymerase ε (POLE) ultra-mutated, microsatellite instability (MSI), copy number low and copy number high [34]
Summary
Cancer is responsible for 1 in 6 deaths worldwide, and is thereby the second leading cause of mortality [1]. Even though technological advancements have improved standard therapies, mortality rates for endometrial cancer are still increasing. Over the last 15 years, there has been an increase in endometrial cancer related deaths of about 15% [1,2,3,4,5], supporting the notion that therapies for endometrial cancer need to be urgently revised and improved. The biochemical antagonists of protein kinases, the protein phosphatases, have more recently come into the limelight as potential targets in cancer, in type II endometrial carcinomas, where the tumour suppressive phosphatase protein phosphatase type 2A (PP2A) is frequently mutated. We argue that targeted therapies, that take the tumour type and molecular profile of endometrial cancers into account, should be implemented on a more rational basis in clinical trials
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