Prostate cancer is a highly heterogeneous disease, with some tumors growing slowly and others progressing rapidly to metastatic, castration-resistant stages. This presents an urgent need for continued stratification of prostate cancers into biologically and clinically relevant subgroups that can inform prognosis and treatment strategies.
The identification of gene fusions formed due to chromosome rearrangements has provided critical insights into prostate cancer biology and helped shape molecular subclassifications. The most common of these are the ETS family of gene fusions, occurring in approximately 50 percent of cases.
More recently, advances in high-throughput sequencing have uncovered rare but targetable non-ETS gene fusions, including those involving RAF kinases and pseudogenes. In particular, the discovery of fusions such as SLC45A3-BRAF, ESRP1-RAF1, and KLK4-KLKP1 has expanded the spectrum of oncogenic drivers and illuminated novel opportunities for precision medicine in prostate cancer.
In parallel with these discoveries, the Cancer Genome Atlas and other large-scale sequencing efforts have led to the development of a comprehensive molecular taxonomy for prostate cancer. This classification is primarily based on genomic alterations and includes ETS-positive and ETS-negative subtypes.
Let’s take a closer look at the targetable non-ETS gene fusions and their potential as prostate cancer biomarkers.
RAF kinase fusions as therapeutic targets
Researchers investigating transcriptome sequencing of ETS-negative prostate tumors identified two novel gene fusions involving RAF kinases: SLC45A3-BRAF and ESRP1-RAF1. While RAF kinases are well known as drivers of other malignancies, these particular fusions represent a paradigm shift in our understanding of oncogenic drivers in prostate cancer.
Studies show that expression of these particular fusions in prostate cells leads to malignant transformation, increased cell proliferation and survival, and sensitivity to RAF and MEK (MAP2K1) inhibitors. Hence, these results point to the oncogenic potential of RAF pathway activation in prostate cancer and suggest there may be a subset of patients who could benefit from targeted therapies.
Though rare – implicated in less than one percent of prostate cancers – RAF fusions are more prevalent in advanced or therapy-resistant tumors. Their identification supports a broader trend seen in other cancers, such as melanoma and gastric cancer, where RAF fusions both drive disease and predict response to targeted inhibitors.
The pseudogene-associated fusion with biomarker potential
KLK4-KLKP1 is a fusion between the protein-coding KLK4 gene and the non-coding pseudogene KLKP1 – both members of the kallikrein family. This fusion was discovered via transcriptome screening using next-generation sequencing of over 650 prostate cancer samples.
This aberration may be detected in around 32 percent of prostate cancer patients. In a US study, it occurred more frequently in Caucasian than African American patients. In vitro and in vivo studies show that KLK4-KLKP1 enhances cell proliferation, invasion, and migration, as well as intravasation and tumorigenesis.
Importantly, this gene fusion is detectable in urine samples, indicating its potential as a non-invasive biomarker. Given its association with lower PSA levels and younger age at diagnosis – typically less than 50 years of age – it may serve as a screening and early detection tool, especially in ETS-positive patients.
Implications for precision oncology
The identification of rare but actionable gene fusions in prostate cancer demonstrates the importance of comprehensive molecular profiling. These findings have profound implications for the future of precision oncology:
Diagnostic stratification: KLK4-KLKP1 and RAF fusions can help refine molecular subtypes and predict clinical outcomes.
Therapeutic targeting: RAF fusion–positive tumors may benefit from MEK or RAF inhibitors, expanding treatment options beyond androgen deprivation.
Noninvasive monitoring: Urine-based detection of KLK4-KLKP1 provides a promising avenue for screening and monitoring disease recurrence.
Looking forward, integration of transcriptomic data into clinical workflows will be essential for identifying patients who can benefit from personalized therapies and for uncovering new therapeutic targets in molecular disease subtypes.
We should expect future research to continue to focus on comprehensive transcriptomic analyses, particularly in ETS-negative and treatment-resistant tumors, to uncover additional rare drivers. These efforts will be critical in ushering in an era of personalized therapy for prostate cancer patients, guided by the unique molecular fingerprint of their disease.
Nallasivam Palanisamy is an Associate Scientist at the Department of Urology, Henry Ford Health, and Associate Professor of Research at Michigan State University.
Newsletters
Receive the latest pathologist news, personalities, education, and career development – weekly to your inbox.
