Mechanistic Rationale for Inhibition of Poly(ADP-Ribose) Polymerase in ETS Gene Fusion-Positive Prostate Cancer

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• 作者：J.  ; Chad Brenner¹ ; ² ; ³ ; ¹¹ ; Bushra Ateeq¹ ; ² ; ¹¹ ; Yong Li¹ ; ² ; Anastasia  ; K. Yocum¹ ; ² ; ⁸ ; Qi Cao¹ ; ² ; Irfan  ; A. Asangani¹ ; Sonam Patel¹ ; Xiaoju Wang¹ ; ² ; Hallie Liang¹ ; Jindan Yu¹ ; ² ; ⁷ ; Nallasivam Palanisamy¹ ; ² ; ⁹ ; Javed Siddiqui¹ ; ² ; ⁷ ; Wei Yan¹ ; ² ; Xuhong Cao¹ ; ⁴ ; Rohit Mehra¹ ; ² ; Aaron Sabolch⁵ ; Venkatesha Basrur¹ ; ² ; Robert  ; J. Lonigro¹ ; ² ; Jun Yang¹⁰ ; Scott  ; A. Tomlins¹ ; ² ; Christopher  ; A. Maher¹ ; ² ; ⁶ ; Kojo  ; S.J. Elenitoba-Johnson² ; Maha Hussain⁷ ; ⁸ ; ⁹ ; Nora  ; M. Navone¹⁰ ; Kenneth  ; J. Pienta¹ ; ³ ; ⁷ ; ⁸ ; ⁹ ; Sooryanarayana Varambally¹ ; ² ; ⁸ ; Felix  ; Y. Feng¹ ; ⁵ ; ⁹ ; Arul  ; M. Chinnaiyan¹ ; ² ; ³ ; ⁴ ; ⁸ ; ⁹ ; ^{arul@umich.edu"" rel=""nofollow}
• 刊名：Cancer Cell
• 出版年：2011
• 出版时间：17 May 2011
• 年：2011
• 卷：19
• 期：5
• 页码：664-678
• 全文大小：1220 K

文摘

Summary

Recurrent fusions of ETS genes are considered driving mutations in a diverse array of cancers, including Ewing's sarcoma, acute myeloid leukemia, and prostate cancer. We investigate the mechanisms by which ETS fusions mediate their effects, and find that the product of the predominant ETS gene fusion, TMPRSS2:ERG, interacts in a DNA-independent manner with the enzyme poly (ADP-ribose) polymerase 1 (PARP1) and the catalytic subunit of DNA protein kinase (DNA-PKcs). ETS gene-mediated transcription and cell invasion require PARP1 and DNA-PKcs expression and activity. Importantly, pharmacological inhibition of PARP1 inhibits ETS-positive, but not ETS-negative, prostate cancer xenograft growth. Finally, overexpression of the TMPRSS2:ERG fusion induces DNA damage, which is potentiated by PARP1 inhibition in a manner similar to that of BRCA1/2 deficiency.