Abstract
There is a great need to develop novel approaches to target oncogenic transcription factors with small molecules. Ewing sarcoma is emblematic of this need, as it depends on the continued activity of the EWS-FLI1 transcription factor to maintain the malignant phenotype. We have previously shown that the small molecule trabectedin interferes with EWS-FLI1. Here, we report important mechanistic advances and a second-generation inhibitor to provide insight into the therapeutic targeting of EWS-FLI1. We discovered that trabectedin functionally inactivated EWS-FLI1 by redistributing the protein within the nucleus to the nucleolus. This effect was rooted in the wild-type functions of the EWSR1, compromising the N-terminal half of the chimeric oncoprotein, which is known to be similarly redistributed within the nucleus in the presence of UV light damage. A second-generation trabectedin analogue lurbinectedin (PM01183) caused the same nuclear redistribution of EWS-FLI1, leading to a loss of activity at the promoter, mRNA, and protein levels of expression. Tumor xenograft studies confirmed this effect, and it was increased in combination with irinotecan, leading to tumor regression and replacement of Ewing sarcoma cells with benign fat cells. The net result of combined lurbinectedin and irinotecan treatment was a complete reversal of EWS-FLI1 activity and elimination of established tumors in 30% to 70% of mice after only 11 days of therapy. Our results illustrate the preclinical safety and efficacy of a disease-specific therapy targeting the central oncogenic driver in Ewing sarcoma.
| Original language | English |
|---|---|
| Pages (from-to) | 6657-6668 |
| Number of pages | 12 |
| Journal | Cancer Research |
| Volume | 76 |
| Issue number | 22 |
| DOIs | |
| Publication status | Published - Nov 15 2016 |
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ASJC Scopus subject areas
- Oncology
- Cancer Research
Cite this
Lurbinectedin inactivates the Ewing sarcoma oncoprotein EWS-FLI1 by redistributing it within the nucleus. / Harlow, Matt L.; Maloney, Nichole; Roland, Joseph; Guillen Navarro, Maria Jose; Easton, Matthew K.; Kitchen-Goosen, Susan M.; Boguslawski, Elissa A.; Madaj, Zachary B.; Johnson, Ben K.; Bowman, Megan J.; D'Incalci, Maurizio; Winn, Mary E.; Turner, Lisa; Hostetter, Galen; Galmarini, Carlos María; Aviles, Pablo M.; Grohar, Patrick J.
In: Cancer Research, Vol. 76, No. 22, 15.11.2016, p. 6657-6668.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Lurbinectedin inactivates the Ewing sarcoma oncoprotein EWS-FLI1 by redistributing it within the nucleus
AU - Harlow, Matt L.
AU - Maloney, Nichole
AU - Roland, Joseph
AU - Guillen Navarro, Maria Jose
AU - Easton, Matthew K.
AU - Kitchen-Goosen, Susan M.
AU - Boguslawski, Elissa A.
AU - Madaj, Zachary B.
AU - Johnson, Ben K.
AU - Bowman, Megan J.
AU - D'Incalci, Maurizio
AU - Winn, Mary E.
AU - Turner, Lisa
AU - Hostetter, Galen
AU - Galmarini, Carlos María
AU - Aviles, Pablo M.
AU - Grohar, Patrick J.
PY - 2016/11/15
Y1 - 2016/11/15
N2 - There is a great need to develop novel approaches to target oncogenic transcription factors with small molecules. Ewing sarcoma is emblematic of this need, as it depends on the continued activity of the EWS-FLI1 transcription factor to maintain the malignant phenotype. We have previously shown that the small molecule trabectedin interferes with EWS-FLI1. Here, we report important mechanistic advances and a second-generation inhibitor to provide insight into the therapeutic targeting of EWS-FLI1. We discovered that trabectedin functionally inactivated EWS-FLI1 by redistributing the protein within the nucleus to the nucleolus. This effect was rooted in the wild-type functions of the EWSR1, compromising the N-terminal half of the chimeric oncoprotein, which is known to be similarly redistributed within the nucleus in the presence of UV light damage. A second-generation trabectedin analogue lurbinectedin (PM01183) caused the same nuclear redistribution of EWS-FLI1, leading to a loss of activity at the promoter, mRNA, and protein levels of expression. Tumor xenograft studies confirmed this effect, and it was increased in combination with irinotecan, leading to tumor regression and replacement of Ewing sarcoma cells with benign fat cells. The net result of combined lurbinectedin and irinotecan treatment was a complete reversal of EWS-FLI1 activity and elimination of established tumors in 30% to 70% of mice after only 11 days of therapy. Our results illustrate the preclinical safety and efficacy of a disease-specific therapy targeting the central oncogenic driver in Ewing sarcoma.
AB - There is a great need to develop novel approaches to target oncogenic transcription factors with small molecules. Ewing sarcoma is emblematic of this need, as it depends on the continued activity of the EWS-FLI1 transcription factor to maintain the malignant phenotype. We have previously shown that the small molecule trabectedin interferes with EWS-FLI1. Here, we report important mechanistic advances and a second-generation inhibitor to provide insight into the therapeutic targeting of EWS-FLI1. We discovered that trabectedin functionally inactivated EWS-FLI1 by redistributing the protein within the nucleus to the nucleolus. This effect was rooted in the wild-type functions of the EWSR1, compromising the N-terminal half of the chimeric oncoprotein, which is known to be similarly redistributed within the nucleus in the presence of UV light damage. A second-generation trabectedin analogue lurbinectedin (PM01183) caused the same nuclear redistribution of EWS-FLI1, leading to a loss of activity at the promoter, mRNA, and protein levels of expression. Tumor xenograft studies confirmed this effect, and it was increased in combination with irinotecan, leading to tumor regression and replacement of Ewing sarcoma cells with benign fat cells. The net result of combined lurbinectedin and irinotecan treatment was a complete reversal of EWS-FLI1 activity and elimination of established tumors in 30% to 70% of mice after only 11 days of therapy. Our results illustrate the preclinical safety and efficacy of a disease-specific therapy targeting the central oncogenic driver in Ewing sarcoma.
UR - http://www.scopus.com/inward/record.url?scp=84995495626&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84995495626&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-16-0568
DO - 10.1158/0008-5472.CAN-16-0568
M3 - Article
AN - SCOPUS:84995495626
VL - 76
SP - 6657
EP - 6668
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0008-5472
IS - 22
ER -