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An inhibitor of oxidative phosphorylation exploits cancer vulnerability

Nature Medicinevolume 24pages10361046 (2018) | Download Citation

Abstract

Metabolic reprograming is an emerging hallmark of tumor biology and an actively pursued opportunity in discovery of oncology drugs. Extensive efforts have focused on therapeutic targeting of glycolysis, whereas drugging mitochondrial oxidative phosphorylation (OXPHOS) has remained largely unexplored, partly owing to an incomplete understanding of tumor contexts in which OXPHOS is essential. Here, we report the discovery of IACS-010759, a clinical-grade small-molecule inhibitor of complex I of the mitochondrial electron transport chain. Treatment with IACS-010759 robustly inhibited proliferation and induced apoptosis in models of brain cancer and acute myeloid leukemia (AML) reliant on OXPHOS, likely owing to a combination of energy depletion and reduced aspartate production that leads to impaired nucleotide biosynthesis. In models of brain cancer and AML, tumor growth was potently inhibited in vivo following IACS-010759 treatment at well-tolerated doses. IACS-010759 is currently being evaluated in phase 1 clinical trials in relapsed/refractory AML and solid tumors.

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Acknowledgements

We thank members of the Center for Co-Clinical Trials, Institute for Applied Cancer Science, the Glioblastoma (GBM) and AML/MDS Moon Shots for intellectual and financial support. We would especially like to express our gratitude and appreciation to C. Vellano for his help editing and assembling this manuscript; F. F. Lang and J. Gumin for providing GSC models; C. Kingsley and the MDACC Small Animals Imaging Facility; and N. Satani and E. Lin for validation of antibodies and preparation of samples for analysis, D. Bigner for D423 cells and D. N. Louis for Gli56 cells. P.Mo. was supported by The Agilent Technologies Thought Leader Award. R.A.D., A.-N.A.A., R.S., and J.Hi. were supported by The Medical Research Council (MC_U105663141 and MC_UU_00015/2 to J.Hi.). M.K., S.T., A.L., P.Ma., H.M., and Q.Z. were supported by CPRIT grant RP140218. F.L.M. was supported by the CPRIT RP140612 and National Institutes of Health (NIH) Brain SPORE P50CA127001, and A.C.S. was supported by the Research Scholar Grant RSG1514501CDD. G.F.D. was supported by the American Association for Cancer Research (AACR) 14-90-25 and by the Sheikh Ahmed Bin Zayed Al Nahyan Center for Pancreatic Cancer Grant. This work was supported in part by the Leukemia & Lymphoma Society through its Therapy Acceleration Program (TAP) and by the MD Anderson Moon Shots program.

Author information

Author notes

    • Pietro Morlacchi

    Present address: Agilent Technologies Inc., Lexington, MA, USA

  1. These authors contributed equally: Jennifer R. Molina, Yuting Sun, Philip Jones, M. Emilia Di Francesco, Joseph R. Marszalek.

Affiliations

  1. Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    • Jennifer R. Molina
    • , Yuting Sun
    • , Marina Protopopova
    • , Sonal Gera
    • , Madhavi Bandi
    • , Christopher Bristow
    • , Timothy McAfoos
    • , Pietro Morlacchi
    • , Jennifer Bardenhagen
    • , Christopher Carroll
    • , Edward Chang
    • , Jason B. Cross
    • , Barbara Czako
    • , Angela Deem
    • , Ningping Feng
    • , Guang Gao
    • , Jason Gay
    • , Mary Geck Do
    • , Jennifer Greer
    • , Virginia Giuliani
    • , Jing Han
    • , Sha Huang
    • , Yongying Jiang
    • , Zhijun Kang
    • , Tin Khor
    • , Gang Liu
    • , Timothy Lofton
    • , Mikhila Mahendra
    • , Robert Mullinax
    • , Michael Peoples
    • , Alessia Petrocchi
    • , Thomas Shi
    • , Melinda Smith
    • , Jay Theroff
    • , Quanyun Xu
    • , Carlo Toniatti
    • , Giulio F. Draetta
    • , Timothy P. Heffernan
    • , Philip Jones
    • , M. Emilia Di Francesco
    •  & Joseph R. Marszalek
  2. Center for Co-Clinical Trials, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    • Jennifer R. Molina
    • , Yuting Sun
    • , Marina Protopopova
    • , Sonal Gera
    • , Madhavi Bandi
    • , Christopher Bristow
    • , Edward Chang
    • , Angela Deem
    • , Ningping Feng
    • , Guang Gao
    • , Jason Gay
    • , Virginia Giuliani
    • , Jing Han
    • , Tin Khor
    • , Mikhila Mahendra
    • , Robert Mullinax
    • , Michael Peoples
    • , Thomas Shi
    • , Melinda Smith
    • , Carlo Toniatti
    • , Giulio F. Draetta
    • , Timothy P. Heffernan
    •  & Joseph R. Marszalek
  3. Department of Cancer Imaging Systems, University of Texas MD Cancer Center, Houston, TX, USA

    • Jeffrey Ackroyd
    • , Yu-Hsi Lin
    •  & Florian Muller
  4. Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Wellcome Trust/MRC Building, Cambridge Biomedical Campus, Cambridge, UK

    • Ahmed-Noor A. Agip
    • , Judy Hirst
    •  & Riccardo Serreli
  5. Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    • Gheath Al-Atrash
    •  & Stefan Ciurea
  6. Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    • John Asara
  7. Department of Neuro-Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    • Caroline C. Carrillo
    • , John Frederick de Groot
    • , Jian-Wen Dong
    •  & Verlene K. Henry
  8. Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    • Naval Daver
    • , Lina Han
    • , Helen Ma
    • , Polina Matre
    • , Yoko Tabe
    • , Qi Zhang
    •  & Marina Konopleva
  9. Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    • Sergej Konoplev
  10. Department of Nutritional Sciences, University of Texas at Austin, Austin, TX, USA

    • Alessia Lodi
    •  & Stefano Tiziani
  11. Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    • Jaime Rodriguez-Canale
  12. Department of Next Generation Hematology Laboratory Medicine, Department of Laboratory Medicine, Juntendo University School of Medicine, Tokyo, Japan

    • Yoko Tabe
  13. Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    • Ronald A. DePinho
  14. Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    • Giulio F. Draetta

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Contributions

The studies were designed with input from J.R.Ma., J.R.Mo., Y.S., M.Pr., M.B., J.Ha., C.B., P.Mo., J.Hi., M.K., P.J., M.E.D.F., C.T., T.P.H., G.F.D., and F.M. In vitro experiments were performed by J.R.Ma, J.R.Mo., V.G., L.Ha., Y.T., Y.S., M.Pr., S.G., M.M., T.K., M.B., P.Mo., J.B., G.G., M.G.D., J.Ha., Y.J., T.L., H.M., P.Ma., M.Pe., R.S., T.S., M.S., V.K.H., C.C.C., and Q.Z. IACS-010759 was developed and conceived by M.E.D.F., T.M., C.C., B.C., G.L., Z.K., A.P., J.T., and P.J. In vivo studies were performed by Y-H. L., N.F., J.Ga., J.Gr., and R.M. Immunohistochemistry was performed by J. Ac., E.C., S.K., and J.R-C. Computational chemistry was performed by J.Hi. and J.B.C. Pharmacokinetic analysis was performed by S.H., Q.X., and Y.J. FACS data analysis was performed by J.R.Mo. and S.G. Glioma stem cell work was performed by Y.S., T.S., J-W.D., V.K.H, J.F.d.G., and C.C.C. Bioinformatic analysis was performed by C.B. Clinical positioning in AML was designed by M.K., N.D., J.R.Ma, M.E.D., and P.J. Metabolomic data for glycolysis deficient was generated by Y.S., C.B., and J.As. and for leukemia by J.R.Mo., S.T., A.L., and P.Mo. Stable-isotope labeling study design, analysis and interpretation was performed by P. Mo. Mouse complex I assays were designed and performed by J.Hi., A.-N.A.A., and R.S. Normal bone marrow samples were provided by S.C. and G.A-A. Writing and preparation of the manuscript and figures were performed by J.R.Ma., J.R.Mo., T.P.H., R.A.D., A.D., Y.S., M.E.D.F., M.K., P. Mo., and P.J.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Joseph R. Marszalek.

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https://doi.org/10.1038/s41591-018-0052-4