Passenger deletions generate therapeutic vulnerabilities in cancer (original) (raw)

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Acknowledgements

We thank K. Ligon, C. Maire, D. N. Louis, J. Kim and G. Mohapatra for sharing bioinformatics data from their tumour neurosphere banks. We also thank D. Bigner for sharing the D423-MG and D502-MG cell lines and D. N. Louis and J. Kim for sharing the Gli56 cell line. We thank G. Chu and D. Jakubosky for assistance with necropsy and histopathological analysis. F.L.M. was supported by a training grant from the National Institutes of Health (NIH T32-CA009361) and a fellowship from the American Cancer Society (115992-PF-08-261-01-TBE). S.C. was supported by a Dana-Farber Cancer Institute/Harvard Cancer Center Myeloma SPORE career development grant. E.A. was supported by a Howard Hughes Medical Institute Medical Research Fellowship (57006984). V.M. was supported by a Harvard PRISE fellowship. M.A.L. was supported by a Diversity in Health-Related research award (3 P01 CA095616-08S1). F.L.M. thanks J. Mohr for assistance with figure preparations. We also thank K. Muller for assistance with manuscript editing. We thank all members of the DePinho and Chin laboratories for suggestions and discussions. This work is supported by the NIH (P01CA95616 to C.B., L.C. and R.A.D.) and by the Ben and Catherine Ivy Foundation (to R.A.D. and L.C.).

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Author notes

  1. Florian L. Muller, Simona Colla and Elisa Aquilanti: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, 77030, Texas, USA
    Florian L. Muller, Simona Colla, Giannicola Genovese, Pingna Deng, Luigi Nezi, Baoli Hu, Jian Hu, Derrick Ong, Eliot Fletcher-Sananikone, Lawrence Kwong, Y. Alan Wang & Lynda Chin
  2. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, 02115, Massachusetts, USA
    Florian L. Muller, Simona Colla, Elisa Aquilanti, Veronica E. Manzo, Giannicola Genovese, Jaclyn Lee, Daniel Eisenson, Rujuta Narurkar, Pingna Deng, Luigi Nezi, Michelle A. Lee, Baoli Hu, Jian Hu, Ergun Sahin, Derrick Ong, Eliot Fletcher-Sananikone, Dennis Ho, Lawrence Kwong, Y. Alan Wang, Lynda Chin & Ronald A. DePinho
  3. Department of Genetics and Medicine, Harvard Medical School, Boston, 02115, Massachusetts, USA
    Florian L. Muller, Simona Colla, Jian Hu, Ergun Sahin, Derrick Ong, Dennis Ho & Ronald A. DePinho
  4. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, 02115, Massachusetts, USA
    Michelle A. Lee
  5. Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, 02115, Massachusetts, USA
    Baoli Hu, Y. Alan Wang, Lynda Chin & Ronald A. DePinho
  6. Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, 10065, New York, USA
    Cameron Brennan
  7. Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, 77030, Texas, USA
    Ronald A. DePinho

Authors

  1. Florian L. Muller
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  2. Simona Colla
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  3. Elisa Aquilanti
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  4. Veronica E. Manzo
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  5. Giannicola Genovese
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  6. Jaclyn Lee
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  7. Daniel Eisenson
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  8. Rujuta Narurkar
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  9. Pingna Deng
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  10. Luigi Nezi
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  11. Michelle A. Lee
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  12. Baoli Hu
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  13. Jian Hu
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  14. Ergun Sahin
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  15. Derrick Ong
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  16. Eliot Fletcher-Sananikone
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  17. Dennis Ho
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  18. Lawrence Kwong
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  19. Cameron Brennan
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  20. Y. Alan Wang
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  21. Lynda Chin
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  22. Ronald A. DePinho
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Contributions

F.L.M. and R.A.D. generated the original hypothesis. F.L.M. performed all bioinformatics work, including scanning the TCGA data set (with initial assistance from J.H.) and identifying candidates for collateral lethality, with the exception of KLHL9, which was identified by E.F.-S. E.A. obtained the D423-MG cell line and designed and carried out the pLKO and pGIPZ shRNA experiments. S.C. designed and performed all shRNA experiments with the inducible vectors and rescue experiments. F.L.M. and E.A. identified PHAH, F.L.M. procured the compound, and F.L.M. and S.C. performed all inhibitor treatment experiments. L.N. generated shRNA-resistant constructs of ENO2. S.C., D.O. and E.F.-S. performed cell cycle and apoptosis assays. R.N., V.M., D.E., P.D. and J.L. performed cell culture, crystal violet staining, western blotting and associated experiments and assisted in the preparation of figures. C.B. provided extensive unpublished genomic data and reagents from his primary brain tumour and neurosphere bank for Supplementary Table 1. E.A., M.A.L., B.H. and G.G. performed tumour cell injections. D.H., E.S., L.K., Y.A.W. and L.C. provided intellectual contributions throughout the project. F.L.M., E.A., S.C., Y.A.W., L.C. and R.A.D. wrote the paper.

Corresponding author

Correspondence toRonald A. DePinho.

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The authors declare no competing financial interests.

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Muller, F., Colla, S., Aquilanti, E. et al. Passenger deletions generate therapeutic vulnerabilities in cancer.Nature 488, 337–342 (2012). https://doi.org/10.1038/nature11331

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