Therapeutic Targeting of ETS Rearranged Cancers.

ETS Transcription Factors;Targeted Therapeutics;DNA Repair;PARP1;DNA-PKcs;Gene Fusion;Molecular;Cellular and Developmental Biology;Science;Cellular & Molecular Biology

Brenner, John ChadCarey, Thomas E. ;

University of Michigan

关键词: ETS Transcription Factors;    Targeted Therapeutics;    DNA Repair;    PARP1;    DNA-PKcs;    Gene Fusion;    Molecular;    Cellular and Developmental Biology;    Science;    Cellular & Molecular Biology;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/94039/chadbren_1.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

A rate limiting step in the realization of personalized medicine is the ability to create viable therapeutic strategies for specific molecular lesions. Among the unique types of molecular lesions that are currently considered ;;undruggable” is a class of proteins called transcription factors, which broadly serve as regulators of gene expression. Recurrent fusions of ETS transcription factors are driving events in a diverse array of cancers including prostate cancer (PCa) and Ewing’s sarcoma family of tumors (ESFTs). Here, I show that the protein products of ETS gene fusions from both PCa (TMPRSS2-ERG) and ESFT (EWS-ERG and EWS-FLI1) interact with the enzymes poly(ADP-ribose) polymerase1 (PARP1) and DNA protein kinase catalytic subunit (DNA-PKcs). ETS gene-mediated transcription, invasion and metastasis require PARP1 and DNA-PKcs expression and activity. Importantly, pharmacological inhibition of PARP1 inhibits ETS-positive, but not ETS-negative, PCa and ESFT xenograft growth. Addition of a PARP inhibitor to the second-line ESFT chemotherapeutic agent temozolomide resulted in complete and sustained responses of all treated tumors in one ETS positive xenograft model. Mechanistically, ETS fusion overexpression induces DNA damage, which is potentiated by PARP1 inhibition in a manner similar to that of BRCA1/2 deficiency. Notably, EWS-FLI1 fusion proteins acted in a positive feedback loop to maintain the expression of PARP1, which was required for EWS-FLI-mediated transcription, thereby enforcing oncogene-dependent sensitivity to PARP-1 inhibition. Because PARP inhibition inhibits ERG indirectly, we further sought to inhibit ERG directly. We identified a consensus ERG-binding peptide that disrupts the ERG:DNA-PKcs interaction from a phage display library. X-ray crystallography confirmed the interaction residues are accessible and led to the first structure of an ETS protein without DNA. ERG inhibitory peptides were found to efficiently disrupt ERG-mediated transcription, DNA damage and cell invasion as well as suppress tumor growth, intravasation and metastasis. Taken together, this work creates a viable therapeutic strategy for targeting transcription factors – historically considered ;;undruggable” – based on mechanistic rationale and a strategy that can be used to build therapeutics against other transcription factors. As such, this thesis continues to build on the work of many generations of researchers towards the ultimate goal of personalized medicine.