Targeting RET Kinase in Neuroendocrine Prostate Cancer

Halena R. VanDeusen, Johnny R. Ramroop, Katherine L. Morel, Song Yi Bae, Anjali V. Sheahan, Zoi Sychev, Nathan A. Lau, Larry C. Cheng, Victor M. Tan, Zhen Li, Ashley Petersen, John K. Lee, Jung Wook Park, Rendong Yang, Justin H. Hwang, Ilsa Coleman, Owen N. Witte, Colm Morrissey, Eva Corey, Peter S. NelsonLeigh Ellis, Justin M. Drake

Research output: Contribution to journalArticle

Abstract

The increased treatment of metastatic castration-resistant prostate cancer (mCRPC) with second-generation antiandrogen 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 suggests kinase signaling may be an important driver of NEPC. To identify targetable kinases in NEPC, we performed global phosphoproteomics comparing several AR-independent to AR-dependent prostate cancer cell lines and identified multiple altered signaling pathways, including enrichment of RET kinase activity in the AR-independent cell lines. Clinical NEPC patient samples and NEPC patient-derived xenografts displayed upregulated RET transcript and RET pathway activity. Genetic knockdown or pharmacologic 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. Currently, there are limited treatment options for patients with aggressive neuroendocrine prostate cancer and none are curative. IMPLICATIONS: Identification of aberrantly expressed RET kinase as a driver of tumor growth in multiple models of NEPC provides a significant rationale for testing the clinical application of RET inhibitors in patients with AVPC.

Original languageEnglish (US)
Pages (from-to)1176-1188
Number of pages13
JournalMolecular cancer research : MCR
Volume18
Issue number8
DOIs
StatePublished - Aug 1 2020

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    VanDeusen, H. R., Ramroop, J. R., Morel, K. L., Bae, S. Y., Sheahan, A. V., Sychev, Z., Lau, N. A., Cheng, L. C., Tan, V. M., Li, Z., Petersen, A., Lee, J. K., Park, J. W., Yang, R., Hwang, J. H., Coleman, I., Witte, O. N., Morrissey, C., Corey, E., ... Drake, J. M. (2020). Targeting RET Kinase in Neuroendocrine Prostate Cancer. Molecular cancer research : MCR, 18(8), 1176-1188. https://doi.org/10.1158/1541-7786.MCR-19-1245