Targeting RET Kinase in Neuroendocrine Prostate Cancer.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • VanDeusen, HR; Ramroop, JR; Morel, KL; Bae, SY; Sheahan, AV; Sychev, Z; Lau, NA; Cheng, LC; Tan, VM; Li, Z; Petersen, A; Lee, JK; Park, JW; Yang, R; Hwang, JH; Coleman, I; Witte, ON; Morrissey, C; Corey, E; Nelson, PS; Ellis, L; Drake, JM

Published Date

  • August 2020

Published In

Volume / Issue

  • 18 / 8

Start / End Page

  • 1176 - 1188

PubMed ID

  • 32461304

Pubmed Central ID

  • PMC7415621

Electronic International Standard Serial Number (EISSN)

  • 1557-3125

Digital Object Identifier (DOI)

  • 10.1158/1541-7786.MCR-19-1245

Language

  • eng

Conference Location

  • United States