MEK-ERK signaling is a therapeutic target in metastatic castration resistant prostate cancer

Prostate Cancer and Prostatic Diseases
Nicholas G NickolsMatthew B Rettig

Abstract

Metastatic castration resistant prostate cancer (mCRPC) is incurable and progression after drugs that target the androgen receptor-signaling axis is inevitable. Thus, there is an urgent need to develop more effective treatments beyond hormonal manipulation. We sought to identify activated kinases in mCRPC as therapeutic targets for existing, approved agents, with the goal of identifying candidate drugs for rapid translation into proof of concept Phase II trials in mCRPC. To identify evidence of activation of druggable kinases in these patients, we compared mRNA expression from metastatic biopsies of patients with mCRPC (n = 101) to mRNA expression in localized prostate from TCGA and used this analysis to infer differential kinase activity. In addition, we assessed the differential phosphorylation levels for key MAPK pathway kinases between mCRPC and localized prostate cancers. Transcriptomic profiling of 101 patients with mCRPC as compared to patients with localized prostate cancer identified evidence of hyperactive ERK1, and whole genome sequencing revealed frequent amplifications of members of the MAPK pathway in 32% of this cohort. Next, we confirmed elevated levels of phosphorylated ERK1/2 in castration resistant prostate c...Continue Reading

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Citations

Feb 23, 2020·BioMed Research International·Zhenxue ZhangFanglin Zhang
Nov 29, 2020·The Journal of Clinical Endocrinology and Metabolism·Juan M Jiménez-VacasRaúl M Luque
Nov 21, 2020·Biochimica Et Biophysica Acta. Reviews on Cancer·Milena Rizzo
Mar 7, 2021·Cancers·Amaal Ali, George Kulik
Apr 4, 2021·Cancers·Lisa Maria MustachioJason Roszik
Jul 15, 2021·Nature Cancer·Joaquin MateoHimisha Beltran

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Methods Mentioned

BETA
biopsies
RNA-seq
biopsy
xenografts

Clinical Trials Mentioned

NCT02881242
NCT02432001

Software Mentioned

TumorMap
VIPER
Virtual Inference of Protein activity by Enriched Regulon ( VI...

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