Therapeutic strategy for targeting recurrent oncogenic kinase gene fusions in prostate cancer.
Authors: Turaga Ravi Chakra , Jagannathan Murali Shivani , Karre Bharath Kumar , Ivan Cristina , Sima Chao , Abera Asfetaw , Radovich Milan , O'Neill Heather 
Published: June 2024

5093

Background: Prostate cancer is known to be the second leading cause of death for men in the United States. Studies so far have indicated androgen signaling to be a crucial pathway in prostate cancer progression. The primary goal of this study was to profile and sort the oncogenic kinase gene fusions by their clinical and genetic characteristics. We also sought to identify molecular alterations of the androgen receptor (AR), including fusions, AR variants, and co-occurring pathogenic variants including mutations, amplifications, and deletions. Methods: We performed molecular profiling with WES and WTS of 8377 prostate cancer tumor tissue and metastatic tumor specimens. Targeted NGS evaluating single nucleotide alterations, copy number alterations, and fusions was performed on these specimens. Results: Our studies identified that out of 8377 tumor samples 128 harbored recurrent, oncogenic kinase fusions (1.5%). Amongst all the kinase gene fusion cases BRAF (0.8%) had the highest number of fusions followed by FGFR2 (0.2%), AKT3 (0.2%) and RAF (0.1%). All BRAF & RAF1 fusions functioned as 3` partners and retained the kinase domain. For fusions involving FGFR2 and AKT3, they participated as both 5’ and 3’ partners, retaining the kinase domain. We then characterized the fusions based on their concordant mutational status with high frequency of TP53 (23.3%) and PI3KCA (9.2%) mutations. We next examined AR status due to its pivotal role in prostate cancer progression and found that AR pathogenic mutations only accounted for 4.2% of the total number of fusion cases. For BRAF fusion targets, it was noted that very few AR point mutations (W742C and H875Y), known to cause resistance to AR antagonists, associated with it. Other fusions targets like FGFR2, AKT3 and RAF1 also harbored very few co-occurring pathogenic mutations in AR. Another constitutively active variant of androgen receptor that lacks the androgen binding domain is ARv7 is observed in 15.6% of cases. Conclusions: Prostate cancer has been very difficult to treat, and first line of treatment so far has mainly included androgen related therapy and chemotherapy. However, our studies reveal the presence of recurrent gene fusions in prostate cancer that may likely play a crucial role in tumor progression. BRAF had the highest number of kinase fusion cases followed by FGFR2, AKT3 and RAF1. Interestingly for cases with BRAF fusions, it was observed that it retained the kinase domain, harbored no AR fusions or alterations and had very few co-occurring mutations. Similarly other fusions targets like FGFR2, AKT3 and RAF1 also had very few AR mutations and 79 % of kinase fusions retained the kinase domain. Our data suggests that the fusion targets may be functioning in an AR independent mechanism, mediated by constitutively active kinase domain present in these fusions. Repurposing kinase inhibitors in combination with AR inhibitors might be a new therapeutic opportunity.