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Acute Leukemias

Efficacy of the investigational mTOR kinase inhibitor MLN0128/INK128 in models of B-cell acute lymphoblastic leukemia

Leukemia volume 27, pages 586–594 (2013)Cite this article

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Abstract

The mechanistic target of rapamycin (mTOR) is a serine/threonine kinase whose activity contributes to leukemia proliferation and survival. Compounds targeting the mTOR active site inhibit rapamycin-resistant functions and have enhanced anticancer activity in mouse models. MLN0128 (formerly known as INK128) is a novel, orally active mTOR kinase inhibitor currently in clinical development. Here, we evaluated MLN0128 in preclinical models of B-cell acute lymphoblastic leukemia (B-ALL). MLN0128 suppressed proliferation of B-ALL cell lines in vitro and reduced colony formation by primary human leukemia cells from adult and pediatric B-ALL patients. MLN0128 also boosted the efficacy of dasatinib (DA) in Philadelphia Chromosome-positive (Ph+) specimens. In a syngeneic mouse model of lymphoid BCR-ABL+ disease, daily oral dosing of MLN0128 rapidly cleared leukemic outgrowth. In primary xenografts of Ph+ B-ALL specimens, MLN0128 significantly enhanced the efficacy of DA. In non-Ph B-ALL xenografts, single agent MLN0128 had a cytostatic effect that was most pronounced in mice with low disease burden. In all in vivo models, MLN0128 was well tolerated and did not suppress endogenous bone marrow proliferation. These findings support the rationale for clinical testing of MLN0128 in both adult and pediatric B-ALL and provide insight towards optimizing therapeutic efficacy of mTOR kinase inhibitors.

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References

  1. McCubrey JA, Steelman LS, Abrams SL, Bertrand FE, Ludwig DE, Basecke J et al. Targeting survival cascades induced by activation of Ras/Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways for effective leukemia therapy. Leukemia 2008; 22: 708–722.

    Article  CAS  Google Scholar 

  2. Chapuis N, Tamburini J, Green AS, Willems L, Bardet V, Park S et al. Perspectives on inhibiting mTOR as a future treatment strategy for hematological malignancies. Leukemia 2010; 24: 1686–1699.

    Article  CAS  Google Scholar 

  3. Steelman LS, Abrams SL, Whelan J, Bertrand FE, Ludwig DE, Basecke J et al. Contributions of the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways to leukemia. Leukemia 2008; 22: 686–707.

    Article  CAS  Google Scholar 

  4. Vu C, Fruman DA . Target of rapamycin signaling in leukemia and lymphoma. Clin Cancer Res 2010; 16: 5374–5380.

    Article  CAS  Google Scholar 

  5. Zoncu R, Efeyan A, Sabatini DM . mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol 2011; 12: 21–35.

    Article  CAS  Google Scholar 

  6. Thoreen CC, Sabatini DM . Rapamycin inhibits mTORC1, but not completely. Autophagy 2009; 5: 725–726.

    Article  CAS  Google Scholar 

  7. Altman JK, Sassano A, Kaur S, Glaser H, Kroczynska B, Redig AJ et al. Dual mTORC2/mTORC1 targeting results in potent suppressive effects on acute myeloid leukemia (AML) progenitors. Clin Cancer Res 2011; 17: 4378–4388.

    Article  CAS  Google Scholar 

  8. Carayol N, Vakana E, Sassano A, Kaur S, Goussetis DJ, Glaser H et al. Critical roles for mTORC2- and rapamycin-insensitive mTORC1-complexes in growth and survival of BCR-ABL-expressing leukemic cells. Proc Natl Acad Sci USA 2010; 107: 12469–12474.

    Article  CAS  Google Scholar 

  9. Janes MR, Limon JJ, So L, Chen J, Lim RJ, Chavez MA et al. Effective and selective targeting of leukemia cells using a TORC1/2 kinase inhibitor. Nat Med 2010; 16: 205–213.

    Article  CAS  Google Scholar 

  10. Engelman JA, Luo J, Cantley LC . The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet 2006; 7: 619.

    Article  Google Scholar 

  11. Kharas MG, Janes MR, Scarfone VM, Lilly MB, Knight ZA, Shokat KM et al. Ablation of PI3K blocks BCR-ABL leukemogenesis in mice, and a dual PI3K/mTOR inhibitor prevents expansion of human BCR-ABL+ leukemia cells. J Clin Invest 2008; 118: 3038–3050.

    Article  CAS  Google Scholar 

  12. Garrett JT, Chakrabarty A, Arteaga CL . Will PI3K pathway inhibitors be effective as single agents in patients with cancer? Oncotarget 2011; 2: 1314–1321.

    Article  Google Scholar 

  13. Liu P, Cheng H, Roberts TM, Zhao JJ . Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov 2009; 8: 627–644.

    Article  CAS  Google Scholar 

  14. Fan QW . A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma. Cancer Cell 2006; 9: 341–349.

    Article  CAS  Google Scholar 

  15. Maira SM, Stauffer F, Brueggen J, Furet P, Schnell C, Fritsch C et al. Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity. Mol Cancer Ther 2008; 7: 1851–1863.

    Article  CAS  Google Scholar 

  16. Markman B, Tabernero J, Krop I, Shapiro GI, Siu L, Chen LC et al. Phase I safety, pharmacokinetic, and pharmacodynamic study of the oral phosphatidylinositol-3-kinase and mTOR inhibitor BGT226 in patients with advanced solid tumors. Ann Oncol 2012; 23: 2399–2408.

    Article  CAS  Google Scholar 

  17. Prasad G, Sottero T, Yang X, Mueller S, James CD, Weiss WA et al. Inhibition of PI3K/mTOR pathways in glioblastoma and implications for combination therapy with temozolomide. Neuro Oncol 2011; 13: 384–392.

    Article  CAS  Google Scholar 

  18. Raynaud FI, Eccles S, Clarke PA, Hayes A, Nutley B, Alix S et al. Pharmacologic characterization of a potent inhibitor of class I phosphatidylinositide 3-kinases. Cancer Res 2007; 67: 5840–5850.

    Article  CAS  Google Scholar 

  19. Serra V, Markman B, Scaltriti M, Eichhorn PJ, Valero V, Guzman M et al. NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations. Cancer Res 2008; 68: 8022–8030.

    Article  CAS  Google Scholar 

  20. Wallin JJ, Edgar KA, Guan J, Berry M, Prior WW, Lee L et al. GDC-0980 is a novel class I PI3K/mTOR kinase inhibitor with robust activity in cancer models driven by the PI3K pathway. Mol Cancer Ther 2011; 10: 2426–2436.

    Article  CAS  Google Scholar 

  21. Janes MR, Fruman DA . Targeting TOR dependence in cancer. Oncotarget 2010; 1: 69–76.

    PubMed  PubMed Central  Google Scholar 

  22. Vilar E, Perez-Garcia J, Tabernero J . Pushing the envelope in the mTOR pathway. The second generation of inhibitors. Mol Cancer Ther 2011; 10: 395–403.

    Article  CAS  Google Scholar 

  23. Wander SA, Hennessy BT, Slingerland JM . Next-generation mTOR inhibitors in clinical oncology: how pathway complexity informs therapeutic strategy. J Clin Invest 2011; 121: 1231–1241.

    Article  CAS  Google Scholar 

  24. Hsieh AC, Liu Y, Edlind MP, Ingolia NT, Janes MR, Sher A et al. The translational landscape of mTOR signalling steers cancer initiation and metastasis. Nature 2012; 485: 55–61.

    Article  CAS  Google Scholar 

  25. Garcia-Garcia C, Ibrahim YH, Serra V, Calvo MT, Guzman M, Grueso J et al. Dual mTORC1/2 and HER2 blockade results in antitumor activity in preclinical models of breast cancer resistant to anti-HER2 therapy. Clin Cancer Res 2012; 18: 2603–2612.

    Article  CAS  Google Scholar 

  26. Pui CH, Robison LL, Look AT . Acute lymphoblastic leukaemia. Lancet 2008; 371: 1030–1043.

    Article  CAS  Google Scholar 

  27. Apsel B, Blair JA, Gonzalez B, Nazif TM, Feldman ME, Aizenstein B et al. Targeted polypharmacology: discovery of dual inhibitors of tyrosine and phosphoinositide kinases. Nat Chem Biol 2008; 4: 691–699.

    Article  CAS  Google Scholar 

  28. Janes MR, Fruman DA . The in vivo evaluation of active-site TOR inhibitors in models of BCR-ABL+ leukemia. Methods Mol Biol 2012; 821: 251–265.

    Article  CAS  Google Scholar 

  29. Jessen K, Wang S, Kessler L, Guo X, Kucharski J, Staunton J et al. INK128 is a potent and selective TORC1/2 inhibitor with broad oral antitumor activity. Mol Cancer Ther 2009; 8: B148.

    Article  Google Scholar 

  30. Bonapace L, Bornhauser BC, Schmitz M, Cario G, Ziegler U, Niggli FK et al. Induction of autophagy-dependent necroptosis is required for childhood acute lymphoblastic leukemia cells to overcome glucocorticoid resistance. J Clin Invest 2010; 120: 1310–1323.

    Article  CAS  Google Scholar 

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Acknowledgements

This study was supported by National Institutes of Health grant CA158383 (to DAF), National Institutes of Health training grant T32-CA009054 (to MRJ), a Discovery Grant from the University of California Industry–University Cooperative Research Program (to DAF), a Hope Grant from the Hyundai Hope on Wheels Foundation (to DAF) and a sponsored research agreement from Intellikine (to DAF). We thank Hang Pham, Briana Fitch and Mengrou Lu for help with animal studies, Marina Konopleva for access to clinical leukemia samples at MD Anderson Cancer Center, Jean-Pierre Bourquin for advice on stromal cell support cultures, Dario Campana for hTERT-immortalized BM stromal cells and David Rawlings for non-Ph B-ALL cell lines.

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Authors and Affiliations

  1. Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA, USA

    M R Janes, C Vu, S Mallya, M P Shieh, J J Limon & D A Fruman

  2. Intellikine LLC, La Jolla, CA, USA

    M R Janes, L-S Li, K A Jessen, M B Martin, P Ren, Y Liu & C Rommel

  3. Takeda California, Inc., San Diego, CA, USA

    M R Janes, L-S Li, K A Jessen & M B Martin

  4. Department of Medicine, University of California, Irvine, Irvine, CA, USA

    C Vu, M P Shieh, M B Lilly & L S Sender

  5. Hyundai Cancer Institute, CHOC Children's Hospital, Orange, CA, USA

    L S Sender

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  1. M R Janes
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  2. C Vu
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  3. S Mallya
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  7. K A Jessen
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  8. M B Martin
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  10. M B Lilly
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  12. Y Liu
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Corresponding author

Correspondence to D A Fruman.

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Competing interests

MRJ, LL, KAJ and MBM are employees of Takeda California, a pharmaceutical company involved with the investigation of MLN0128. MRJ, LL, KAJ, MBM, PR, YL and CR were all previous employees of Intellikine, a pharmaceutical company that designed and developed MLN0128 (previously designated INK128). DAF was a scientific advisor to Intellikine in the development and utilization of MLN0128.

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Supplementary Information accompanies the paper on the Leukemia website

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Janes, M., Vu, C., Mallya, S. et al. Efficacy of the investigational mTOR kinase inhibitor MLN0128/INK128 in models of B-cell acute lymphoblastic leukemia. Leukemia 27, 586–594 (2013). https://doi.org/10.1038/leu.2012.276

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