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Abstract 3590: Mechanisms and inhibition RIOK2 for obesity-driven prostate cancer

Publication ,  Conference
Macias, E; Cho, J; Rosowicz, D; Heidari, Z; You, S; Maravilla, EJ; Chi, J-T; Freedland, SJ
Published in: Cancer Research
July 1, 2019

Obesity is associated with greater risk of high-grade prostate cancer (PC), recurrence after therapy, metastases, and PC specific mortality. The fact that obesity is a PC risk factor creates an opportunity to identify and target the mechanisms underlying obesity-enhanced lethal PC. We exploited this link by performing an shRNA in vivo screen in obese mice targeting the entire kinome, which found Right Open Reading Frame Kinase 2 (RIOK2) as essential for PCs in obese mice. We found RIOK2 gene signature is correlated with a 56% increased risk of metastatic PC. Moreover, when we queried only men with a BMI ≥ 30 kg/m2 we found that high levels of RIOK2 gene signature increased the risk of metastasis by an additional 50%. RIOK2, a serine/threonine kinase, is critical for de novo ribosome maturation and assembly, which is essential to maintain the high proliferation rates in cancer cells. Indeed, we found that RIOK2 loss reduced de novo protein synthesis in PC cells and decreased cell viability. Conversely, RIOK2 overexpression enhanced PC cell growth. As our goal is to find actionable PC targets to reduce obesity effects on PC, we conducted a protein structure based compound screen in silico and identified a lead kinase inhibitor of RIOK2 (kiRIOK2). Our lead kiRIOK2 inhibits cell proliferation, protein synthesis, anchorage-independent growth and invasion of multiple PC lines in the µM range. SAR optimized kiRIOK2 have increased efficacy and bioavailability. Our studies are providing probes and mechanistic insights to further investigate the role of RIOK2 in PC biology. In the long-term, this may help mitigate the added risk of obesity on PC metastasis and PC-specific mortality.Citation Format: Everardo Macias, Jiyoon Cho, Drew Rosowicz, Zahra Heidari, Sungyong You, Erick J. Maravilla, Jen-Tsan Chi, Stephen J. Freedland. Mechanisms and inhibition RIOK2 for obesity-driven prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3590.

Duke Scholars

Published In

Cancer Research

DOI

EISSN

1538-7445

ISSN

0008-5472

Publication Date

July 1, 2019

Volume

79

Issue

13_Supplement

Start / End Page

3590 / 3590

Publisher

American Association for Cancer Research (AACR)

Related Subject Headings

  • Oncology & Carcinogenesis
  • 3211 Oncology and carcinogenesis
  • 3101 Biochemistry and cell biology
  • 1112 Oncology and Carcinogenesis
 

Citation

APA
Chicago
ICMJE
MLA
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Macias, E., Cho, J., Rosowicz, D., Heidari, Z., You, S., Maravilla, E. J., … Freedland, S. J. (2019). Abstract 3590: Mechanisms and inhibition RIOK2 for obesity-driven prostate cancer. In Cancer Research (Vol. 79, pp. 3590–3590). American Association for Cancer Research (AACR). https://doi.org/10.1158/1538-7445.am2019-3590
Macias, Everardo, Jiyoon Cho, Drew Rosowicz, Zahra Heidari, Sungyong You, Erick J. Maravilla, Jen-Tsan Chi, and Stephen J. Freedland. “Abstract 3590: Mechanisms and inhibition RIOK2 for obesity-driven prostate cancer.” In Cancer Research, 79:3590–3590. American Association for Cancer Research (AACR), 2019. https://doi.org/10.1158/1538-7445.am2019-3590.
Macias E, Cho J, Rosowicz D, Heidari Z, You S, Maravilla EJ, et al. Abstract 3590: Mechanisms and inhibition RIOK2 for obesity-driven prostate cancer. In: Cancer Research. American Association for Cancer Research (AACR); 2019. p. 3590–3590.
Macias, Everardo, et al. “Abstract 3590: Mechanisms and inhibition RIOK2 for obesity-driven prostate cancer.” Cancer Research, vol. 79, no. 13_Supplement, American Association for Cancer Research (AACR), 2019, pp. 3590–3590. Crossref, doi:10.1158/1538-7445.am2019-3590.
Macias E, Cho J, Rosowicz D, Heidari Z, You S, Maravilla EJ, Chi J-T, Freedland SJ. Abstract 3590: Mechanisms and inhibition RIOK2 for obesity-driven prostate cancer. Cancer Research. American Association for Cancer Research (AACR); 2019. p. 3590–3590.

Published In

Cancer Research

DOI

EISSN

1538-7445

ISSN

0008-5472

Publication Date

July 1, 2019

Volume

79

Issue

13_Supplement

Start / End Page

3590 / 3590

Publisher

American Association for Cancer Research (AACR)

Related Subject Headings

  • Oncology & Carcinogenesis
  • 3211 Oncology and carcinogenesis
  • 3101 Biochemistry and cell biology
  • 1112 Oncology and Carcinogenesis