Endometrial Cancers With Activating KRas Mutations Have Activated Estrogen Signaling and Paradoxical Response to MEK Inhibition.

International Journal of Gynecological Cancer : Official Journal of the International Gynecological Cancer Society
Kari L RingKaren H Lu

Abstract

The aims of this study were to determine if activating KRas mutation alters estrogen signaling in endometrial cancer (EC) and to explore the potential therapeutic impact of these alterations. The Cancer Genome Atlas was queried for changes in estrogen-regulated genes in EC based on KRas mutation status. In vitro studies were conducted to evaluate estrogen receptor α (ERα) phosphorylation changes and related kinase changes in KRas mutant EC cells. The resulting effect on response to MEK inhibition, using trametinib, was evaluated. Immunohistochemistry was performed on KRas mutant and wild-type EC tumors to test estrogen signaling differences. KRas mutant tumors in The Cancer Genome Atlas showed decreased progesterone receptor expression (P = 0.047). Protein analysis in KRas mutant EC cells also showed decreased expression of ERα (P < 0.001) and progesterone receptor (P = 0.001). Although total ERα is decreased in KRas mutant cells, phospho-ERα S118 was increased compared with wild type. Treatment with trametinib in KRas mutant cells increased phospho-ERα S167 and increased expression of estrogen-regulated genes. While MEK inhibition blocked estradiol-stimulated phosphorylation of ERK1/2 and p90RSK in wild-type cells, phospho-ERK...Continue Reading

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Citations

Dec 21, 2019·Nature Communications·Satoshi InoueHiroyuki Mano
Jul 31, 2020·Signal Transduction and Targeted Therapy·Qiao WangXia Zhao
Apr 4, 2021·Cancers·Lisa Maria MustachioJason Roszik
Nov 5, 2021·PloS One·Morgan T WalcheckSean M Ronnekleiv-Kelly

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