RET Kinase Signaling as a Key Switch Toward the Neuroendocrine Phenotype
Technical Report,30 Sep 2018,29 Sep 2019
University of Minnesota Minneapolis United States
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Increased treatment of metastatic castration resistant prostate cancer mCRPC with second-generation anti-androgen therapies ADT has coincided with a greater incidence of lethal, aggressive variant prostate cancer AVPC tumors that have lost androgen receptor AR signaling. AVPC tumors may also express neuroendocrine markers, termed neuroendocrine prostate cancer NEPC. Recent evidence suggests kinase signaling may be an important driver of NEPC. To identify targetable kinases in NEPC, we performed global phosphoproteomics comparing AR-negative to AR-positive prostate cancer cell lines and identified multiple altered signaling pathways, including enrichment of RET kinase activity in the AR-negative cell lines. Clinical NEPC and NEPC patient derived xenografts displayed upregulated RET transcript and RET pathway activity. Pharmacologically inhibiting RET kinase in NEPC models dramatically reduced tumor growth and cell viability in mouse and human NEPC models. Our results suggest that targeting RET in NEPC tumors with high RET expression and may be a novel treatment option.
- Medicine and Medical Research