Background: Prostate epithelium is exquisitely sensitive to the overexpression of the proto-oncogene MYC which causes neoplastic transformation. Indeed, MYC protein is almost universally overexpressed in metastatic castration-resistant prostate cancer (CRPC) making targeting MYC an attractive option for treating advanced stage disease. One of the main effects of MYC in cancer cells is to accelerate proliferative growth via stimulation of high levels of ribosome biogenesis. MYC also regulates and cooperates with PIM kinases to increase the activity of the eIF4F translation initiation complex and MYC-driven tumors are addicted to eIF4E. Here, we investigate the efficacy of a single and dual approach targeting ribosome biogenesis and function to treat prostate cancer (PC).
Experimental design: We employed numerous models of PC, including a novel CRPC patient derived xenograft system, which showed the pre-clinical efficacy of therapies that combine to target MYC directed signaling to the ribosome. CX-5461, a potent, selective and orally bioavailable inhibitor of RNA polymerase I (Pol I) transcription, and CX-6258, a pan-PIM kinase inhibitor, were tested alone and in combination in PC cell lines, in Hi-MYC and PTEN-deficient mouse models and in patient derived xenografts (PDX) and organoids of metastatic tissue obtained from castration-resistant patients.
Results: Oral administration of CX-5461 induced p53 expression and activity and reduced proliferation (Ki-67) and invasion (loss of ductal actin) in Hi-MYC tumors, but not in PTEN null ("low MYC") tumors. While CX-6258 showed limited effect alone in vivo, its combination with CX-5461 further suppressed proliferation and dramatically reduced large invasive lesions in both models. This rational combination strategy significantly inhibited proliferation and induced cell death in PDX of CRPC.
Conclusion: Our results demonstrate preclinical efficacy of targeting the ribosome at multiple levels and provide a new approach for the treatment of MYC-driven PC. In addition, a key conclusion of our study is that the androgen receptor (AR) presence or activity has no significant impact on the therapeutic activity of our novel combination therapy.