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

Abstract

BackgroundMetastatic 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.MethodsTo 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.ResultsTranscriptomic 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 cancer as compared to untreated primary prostate cancer. We observed that the presence of detectable phosphorylated ERK1/2 in the primary tumor is associated with biochemical failure after radical prostatectomy independent of clinicopathologic features. ERK1 is the immediate downstream target of MEK1/2, which is druggable with trametinib, an approved therapeutic for melanoma. Trametinib elicited a profound biochemical and clinical response in a patient who had failed multiple prior treatments for mCRPC.ConclusionsWe conclude that pharmacologic targeting of the MEK/ERK pathway may be a viable treatment strategy for patients with refractory metastatic prostate cancer. An ongoing Phase II trial tests this hypothesis.

Ciliary neurotrophic factor (CNTF) and its receptor (CNTFRα) signal through MAPK/ERK pathway in human prostate tissues: a morphological and biomolecular study

“…the decrease of pERK under rhCNTF stimulation, in normal prostate cellular model. Our data are in line with that of Nickols and colleagues 61 showing a correlation of prostate cancer recurrence with the increase of pERK expression levels. Moreover, the same authors demonstrated that the activation of ERK is characteristic of castration resistant prostate cancer while others found a correlation between increased ERK phosphorylation with both stage T and Gleason grade of prostate cancer.…”

“…Moreover, the same authors demonstrated that the activation of ERK is characteristic of castration resistant prostate cancer while others found a correlation between increased ERK phosphorylation with both stage T and Gleason grade of prostate cancer. 61 , 62 So, we can hypothesize that inhibition of ERK phosphorylation can decrease migration and invasion processes downstream of this pathway. As a result, we can speculate that CNTF promotes epithelium homeostasis via pERK downregulation by an autocrine mechanism in normal prostate glandular basal compartment and that dysregulation of this mechanism could contribute to the onset of prostate cancer.…”

The Impact of Whole Genome Data on Therapeutic Decision-Making in Metastatic Prostate Cancer: A Retrospective Analysis

“…Aside from DDR, the most commonly impacted pathways were Phosphoinositide 3-kinase (PI3K, 7/13 (54%) cases), Mitogen-activated protein kinase (MAPK, 10 (77%) cases) and Wnt (9 (69%) cases) ( Table 2). PI3K and MAPK are intracellular and extracellular signalling pathways, respectively, that are key to the regulation of the cell cycle and, like certain DDR pathways, are therapeutically targetable (manipulable) with inhibitory drugs [30,31]. The Wnt signalling pathway is a cellular pathway involved in cell growth, embryogenesis and cell cycle progression, the activation of which has been implicated in progression to CRPC and treatment resistance [32].…”

Curcumin Inhibits ERK/c-Jun Expressions and Phosphorylation against Endometrial Carcinoma

“…Activation of the ERK pathway is associated with the development of numerous tumors [27]. MAPK/ERK pathway activation and subsequent interactions are highly regulated but may be out of regulation in cancer cells.…”