CELL CYCLE-INDEPENDENT DEATH OF PROSTATE ADENOCARCINOMA IS INDUCED BYTHE TRK TYROSINE KINASE INHIBITOR CEP-751 (KT6587)

Advanced prostate cancer remains largely incurable, primarily because the very low growth fraction present in these tumors makes them genera lly resistant to treatment with standard chemotherapeutic agents that target cell division. Effective therapies should therefore induce deat h of prostate cancer cells, independent of their growth rate. trkA, th e high-affinity tyrosine kinase-linked receptor for nerve growth facto r, has been implicated in prostatic cancer growth and may represent a molecular target for therapeutic agents. At low mg/kg doses, the trk t yrosine kinase inhibitor CEP-751 (KT6587) inhibits prostatic cancer gr owth in nine different animal models independent of the tumor growth r ate, androgen sensitivity, metastatic ability, or state of tumor diffe rentiation. CEP-751 is selective for cancerous versus normal prostate cells and affects the growth of only a limited number of nonprostate t umors. Importantly, CEP-751 induces cell death of prostate cancer cell s in a cell cycle-independent fashion and, therefore, represents a nov el therapeutic approach to the management of both hormone-dependent an d hormone-independent prostate cancer.