Targeting RET Kinase in Neuroendocrine Prostate Cancer
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Aug 01, 2020
- Source ID
- 10.1158/1541-7786.mcr-19-1245
Entities
People
- Anjali V. Sheahan
- Ashley Petersen
- Colm Morrissey
- Eva Corey
- Halena R. VanDeusen
- Ilsa M. Coleman
- John K Lee
- Johnny R. Ramroop
- Jung Wook Park
- Justin H. Hwang
- Justin M Drake
- Katherine L Morel
- Larry C Cheng
- Leigh Ellis
- Nathan A. Lau
- Owen N Witte
- Peter S Nelson
- Rendong Yang
- Song Yi Bae
- Victor M Tan
- Zhen Li
- Zoi Sychev
Organizations
- American Cancer Society
- Dana–Farber Cancer Institute
- Duke University
- Fred Hutchinson Cancer Center
- National Cancer Institute
- National Institutes of Health
- Ohio State University
- Rutgers University
- Stand Up to Cancer
- United States Department of Defense
- University of California, Los Angeles
- University of Minnesota
- University of Washington