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Targeting RET Kinase in Neuroendocrine Prostate Cancer.

Publication ,  Journal Article
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 ...
Published in: Mol Cancer Res
August 2020

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.

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Published In

Mol Cancer Res

DOI

EISSN

1557-3125

Publication Date

August 2020

Volume

18

Issue

8

Start / End Page

1176 / 1188

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Up-Regulation
  • Receptors, Androgen
  • Proto-Oncogene Proteins c-ret
  • Proteomics
  • Prostatic Neoplasms
  • Phosphorylation
  • PC-3 Cells
  • Oncology & Carcinogenesis
  • Mice
 

Citation

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VanDeusen, H. R., Ramroop, J. R., Morel, K. L., Bae, S. Y., Sheahan, A. V., Sychev, Z., … Drake, J. M. (2020). Targeting RET Kinase in Neuroendocrine Prostate Cancer. Mol Cancer Res, 18(8), 1176–1188. https://doi.org/10.1158/1541-7786.MCR-19-1245
VanDeusen, Halena R., Johnny R. Ramroop, Katherine L. Morel, Song Yi Bae, Anjali V. Sheahan, Zoi Sychev, Nathan A. Lau, et al. “Targeting RET Kinase in Neuroendocrine Prostate Cancer.Mol Cancer Res 18, no. 8 (August 2020): 1176–88. https://doi.org/10.1158/1541-7786.MCR-19-1245.
VanDeusen HR, Ramroop JR, Morel KL, Bae SY, Sheahan AV, Sychev Z, et al. Targeting RET Kinase in Neuroendocrine Prostate Cancer. Mol Cancer Res. 2020 Aug;18(8):1176–88.
VanDeusen, Halena R., et al. “Targeting RET Kinase in Neuroendocrine Prostate Cancer.Mol Cancer Res, vol. 18, no. 8, Aug. 2020, pp. 1176–88. Pubmed, doi:10.1158/1541-7786.MCR-19-1245.
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. Targeting RET Kinase in Neuroendocrine Prostate Cancer. Mol Cancer Res. 2020 Aug;18(8):1176–1188.

Published In

Mol Cancer Res

DOI

EISSN

1557-3125

Publication Date

August 2020

Volume

18

Issue

8

Start / End Page

1176 / 1188

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Up-Regulation
  • Receptors, Androgen
  • Proto-Oncogene Proteins c-ret
  • Proteomics
  • Prostatic Neoplasms
  • Phosphorylation
  • PC-3 Cells
  • Oncology & Carcinogenesis
  • Mice