Neurogenic locus notch homolog protein 1 (NOTCH1) is highly expressed in localized high-risk prostate cancers and also metastatic castration-resistant prostate cancer (mCRPC). When chronically activated, NOTCH1 synergizes with multiple oncogenic pathways and promotes metastatic progression of prostate cancer. This signalling axis is a potential therapeutic target in advanced disease.

Stoyanova and colleagues first assessed differences in NOTCH1 expression between benign prostate tissue and prostate cancers at various stages of progression, including low-risk, intermediate-risk, and high-risk tumours, and also CRPC. Immunostaining for notch intracellular domain (NICD1), which is released and translocates to the nucleus after NOTCH1 cleavage where it acts as a transcriptional coactivator, was increased in high-risk disease and CRPC. Levels of NICD1 were also increased in these samples according to western blot analysis, suggesting it has a role in cancer progression.

NOTCH1 synergizes with multiple oncogenic pathways

The investigators then sought to determine whether NICD1 synergizes with known early genetic alterations that occur in prostate cancer using in vivo mouse models of phosphatase and tensin homolog (PTEN) loss and activation of the Ras–Raf–mitogen-activated protein kinase (MAPK) signalling pathway. Overexpression of NICD1 alone was not sufficient to initiate prostate cancer development, but it strongly synergized with myrAKT (mimicking PTEN loss), KRasG12D (which causes Ras–Raf–MAPK activation), and myc proto-oncogene protein (MYC) to cause prostate adenocarcinoma.

Tumours that developed in these models were highly proliferative, exhibited androgen receptor expression, loss of p63 expression, and had high self-renewal activity and metastatic potential. Cells derived from these hormone-naive tumour models were transplanted into immunocompromised mice, which were then surgically castrated. The tumours that developed from these cells continued to grow after androgen deprivation, indicating a castration-resistant phenotype. Gene-set enrichment analysis showed that genes associated with epithelial–mesenchymal transition were enriched.

In vitro, inhibiting γ-secretase, which cleaves NOTCH cell-surface receptors resulting in NICD1 moving to the nucleus, inhibited prostate cancer cell line growth and colony formation. Knocking out NOTCH1 also inhibited cell growth in 22Rv1 cells. In vivo, NOTCH1 inhibition reduced tumour growth.

These data provide evidence that NICD1 synergizes with many pathways implicated in prostate cancer progression and that NOTCH1 is a promising therapeutic target for patients with mCRPC.