by ecancer reporter Clare Sansom

Most prostate cancers are slow growing, confined to the prostate gland and easily treated.

Cancers that have spread beyond the prostate can be treated with anti-androgens to block the growth-promoting action of testosterone; however, most such cancers will resume growth a few years after initiating this hormone therapy.

These tumours are termed castration-resistant prostate cancers (CPRC) and options for treating them are extremely limited.

In many cancers of different types, tumour growth is known to depend on activating mutations in genes encoding tyrosine kinases, and in these cases the kinases concerned provide useful drug targets.

Such activating mutations have rarely been observed in castration-resistant prostate cancer, although the amplification and increased activity of tyrosine kinases still seems to play a role in disease progression.

A protein is only likely to prove a good target for metastatic cancer if it carries the same mutations in all anatomically distinct tumour samples taken from the same patient.

A group of researchers led by Owen Witte from the University of California Los Angeles, Los Angeles, California, USA has now conducted an extensive study of kinase activity in CPRC to determine how it varies both between patients and within each individual patient.

Witte and his co-workers used phosphotyrosine peptide enrichment and quantitative mass spectrometry (MS) to evaluate tyrosine phosphorylation in samples of metastatic CPRC and normal prostate tissue.

The initial analysis included sixteen samples of metastatic CPRC obtained from thirteen different patients, one sample of benign prostate hyperplasia, patient-matched untreated benign and cancerous prostate tissue, and tumour xenografts obtained from prostate cancer cell lines.

The tyrosine phosphorylation patterns obtained from the cell lines differed significantly from all samples taken from patients, suggesting that these were poor models of tyrosine kinase activity in this tumour type.

Furthermore, there was little change in kinase activity between normal prostate tissue and localised, treatment-naïve prostate tumours.

These findings stressed the importance of evaluating kinase activity in metastatic tumours for the selection of drug targets.

The researchers measured kinase activity in prostate tumour metastases taken from different organs in each patient and used unsupervised hierarchical clustering to group the samples by both patient and site of metastasis.

Many different kinases and phosphatases were found to be activated in these samples, but, as expected, few key activating kinase mutations were observed.

Significantly similar patterns of tyrosine phosphorylation were seen in samples from different anatomical sites in each individual patient.

However, similarities were also observed between two of three liver metastases taken from different patients, indicating that the anatomical location of a metastasis may have some effect on its kinase and phosphatase activity.

Analysis of a larger set of 28 anatomically distinct CRPC metastases taken from seven different patients confirmed these findings; patterns of kinase activation varied little between samples taken from the same patient but differed ‘dramatically’ between patients.

Kinases that were found to be consistently phosphorylated, and therefore activated, in samples from at least one patient included SRC; the epidermal growth factor receptor EGFR; arranged during transfection); anaplastic lymphoma kinase ALK and several MAP kinases.

The kinase RET is expressed in neuronal cells, which suggested that the one patient in which its activation was observed may have suffered from a tumour with a small cell neuroendocrine carcinoma (SCNC) phenotype; histological features consistent with this phenotype were then discovered in samples obtained from that patient.

Taken together, these results suggest that individualized therapy with inhibitors of one or more kinases known to be activated in tumour samples taken from a patient with CRPC may benefit that patient, despite the fact that these kinases are activated through signal transduction rather than by mutation.

Inhibitors of a number of kinases identified in this study are already in clinical use, and the researchers predicted that most of the patients in this study might have benefited from treatment with either the SRC inhibitor dasatinib; the MEK inhibitor trametinib; or both drugs.

Reference: Drake, J.M., Graham, N.A., Lee, J.K. and 8 others (2013). Metastatic castration-resistant prostate cancer reveals intrapatient similarity and interpatient heterogeneity of therapeutic kinase targets. Proc. Natl. Acad. Sci. USA 110(49): E4762-9. doi: 10.1073/pnas.1319948110