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Elucidating the Mechanism of RET Kinase Activity in Neuroendocrine Prostate Cancer

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Technical Report,01 Aug 2019,31 Jul 2020

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University of Minnesota Minneapolis United States

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The 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 dependence on androgen receptor AR signaling. These AR independent tumors may also transdifferentiate to express neuroendocrine lineage markers and are termed neuroendocrine prostate cancer NEPC. Recent evidence generated to achieve the aims of this grant suggests RET kinase signaling is an important driver of NEPC. Genetic knockdown or pharmacological inhibition of RET kinase in multiple mouse and human models of NEPC dramatically reduced tumor growth and decreased cell viability. Our results suggest that targeting RET in NEPC tumors with high RET expression could be an effective treatment option. Identification of aberrantly expressed RET kinase as a driver of tumor growth in multiple models of NEPC provides a significant rationale for further understanding how NEPC tumors gain RET expression, defining the mechanism of RET activation, and validation of RET inhibitors alone or as a component of combination therapies to treat NEPC.

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  • Medicine and Medical Research

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