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Targeting c-FOS and DUSP1 abrogates intrinsic resistance to tyrosine-kinase inhibitor therapy in BCR-ABL-induced leukemia

Nature Medicine volume 23, pages 472–482 (2017)Cite this article

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Abstract

Tyrosine-kinase inhibitor (TKI) therapy for human cancers is not curative, and relapse occurs owing to the continued presence of tumor cells, referred to as minimal residual disease (MRD). The survival of MRD stem or progenitor cells in the absence of oncogenic kinase signaling, a phenomenon referred to as intrinsic resistance, depends on diverse growth factors. Here we report that oncogenic kinase and growth-factor signaling converge to induce the expression of the signaling proteins FBJ osteosarcoma oncogene (c-FOS, encoded by Fos) and dual-specificity phosphatase 1 (DUSP1). Genetic deletion of Fos and Dusp1 suppressed tumor growth in a BCR-ABL fusion protein kinase–induced mouse model of chronic myeloid leukemia (CML). Pharmacological inhibition of c-FOS, DUSP1 and BCR-ABL eradicated MRD in multiple in vivo models, as well as in mice xenotransplanted with patient-derived primary CML cells. Growth-factor signaling also conferred TKI resistance and induced FOS and DUSP1 expression in tumor cells modeling other types of kinase-driven leukemias. Our data demonstrate that c-FOS and DUSP1 expression levels determine the threshold of TKI efficacy, such that growth-factor-induced expression of c-FOS and DUSP1 confers intrinsic resistance to TKI therapy in a wide-ranging set of leukemias, and might represent a unifying Achilles' heel of kinase-driven cancers.

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Figure 1: Expression of c-Fos, Dusp1, and Zfp36 constitutes a common signature of imatinib-resistant cells.
Figure 2: Genetic deletion of Fos and Dusp1 increases the response of BCR-ABL-induced leukemia to imatinib.
Figure 3: Chemical inhibition of c-Fos, Dusp1, and BCR-ABL eradicates minimal MRD in mice.
Figure 4: Inhibition of c-Fos, Dusp1, and BCR-ABL selectively eradicates CML cells.
Figure 5: Genetic or chemical inhibition of c-Fos and Dusp1 downregulates the Fos–Jun network while activating Jun–JunD target genes.
Figure 6: Inhibition of Dusp1 activates p38.

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References

  1. Daley, G.Q., Van Etten, R.A. & Baltimore, D. Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. Science 247, 824–830 (1990).

    Article  CAS  PubMed  Google Scholar 

  2. Druker, B.J. et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat. Med. 2, 561–566 (1996).

    Article  CAS  PubMed  Google Scholar 

  3. O'Hare, T., Zabriskie, M.S., Eiring, A.M. & Deininger, M.W. Pushing the limits of targeted therapy in chronic myeloid leukaemia. Nat. Rev. Cancer 12, 513–526 (2012).

    Article  CAS  PubMed  Google Scholar 

  4. Rousselot, P. et al. Imatinib mesylate discontinuation in patients with chronic myelogenous leukemia in complete molecular remission for more than 2 years. Blood 109, 58–60 (2007).

    Article  CAS  PubMed  Google Scholar 

  5. Mahon, F.X. et al. Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncol. 11, 1029–1035 (2010).

    Article  CAS  PubMed  Google Scholar 

  6. Ross, D.M. et al. Safety and efficacy of imatinib cessation for CML patients with stable undetectable minimal residual disease: results from the TWISTER study. Blood 122, 515–522 (2013).

    Article  CAS  PubMed  Google Scholar 

  7. Chu, S. et al. Detection of BCR-ABL kinase mutations in CD34+ cells from chronic myelogenous leukemia patients in complete cytogenetic remission on imatinib mesylate treatment. Blood 105, 2093–2098 (2005).

    Article  CAS  PubMed  Google Scholar 

  8. Savona, M. & Talpaz, M. Getting to the stem of chronic myeloid leukaemia. Nat. Rev. Cancer 8, 341–350 (2008).

    Article  CAS  PubMed  Google Scholar 

  9. Azam, M., Latek, R.R. & Daley, G.Q. Mechanisms of autoinhibition and STI-571/imatinib resistance revealed by mutagenesis of BCR-ABL. Cell 112, 831–843 (2003).

    Article  CAS  PubMed  Google Scholar 

  10. Krause, D.S. & Van Etten, R.A. Tyrosine kinases as targets for cancer therapy. N. Engl. J. Med. 353, 172–187 (2005).

    Article  CAS  PubMed  Google Scholar 

  11. Weinstein, I.B. Cancer. Addiction to oncogenes—the Achilles heal of cancer. Science 297, 63–64 (2002).

    Article  CAS  PubMed  Google Scholar 

  12. Sawyers, C.L. Shifting paradigms: the seeds of oncogene addiction. Nat. Med. 15, 1158–1161 (2009).

    Article  CAS  PubMed  Google Scholar 

  13. Pagliarini, R., Shao, W. & Sellers, W.R. Oncogene addiction: pathways of therapeutic response, resistance, and road maps toward a cure. EMBO Rep. 16, 280–296 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Reddy, A. & Kaelin, W.G., Jr. Using cancer genetics to guide the selection of anticancer drug targets. Curr. Opin. Pharmacol. 2, 366–373 (2002).

    Article  CAS  PubMed  Google Scholar 

  15. Kaelin, W.G., Jr. The concept of synthetic lethality in the context of anticancer therapy. Nat. Rev. Cancer 5, 689–698 (2005).

    Article  CAS  PubMed  Google Scholar 

  16. Kamb, A. Consequences of nonadaptive alterations in cancer. Mol. Biol. Cell 14, 2201–2205 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Mills, G.B., Lu, Y. & Kohn, E.C. Linking molecular therapeutics to molecular diagnostics: inhibition of the FRAP/RAFT/TOR component of the PI3K pathway preferentially blocks PTEN mutant cells in vitro and in vivo. Proc. Natl. Acad. Sci. USA 98, 10031–10033 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Sharma, S.V. & Settleman, J. Exploiting the balance between life and death: targeted cancer therapy and “oncogenic shock”. Biochem. Pharmacol. 80, 666–673 (2010).

    Article  CAS  PubMed  Google Scholar 

  19. Sharma, S.V. & Settleman, J. Oncogene addiction: setting the stage for molecularly targeted cancer therapy. Genes Dev. 21, 3214–3231 (2007).

    Article  CAS  PubMed  Google Scholar 

  20. Corbin, A.S. et al. Human chronic myeloid leukemia stem cells are insensitive to imatinib despite inhibition of BCR-ABL activity. J. Clin. Invest. 121, 396–409 (2011).

    Article  CAS  PubMed  Google Scholar 

  21. Straussman, R. et al. Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature 487, 500–504 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Wilson, T.R. et al. Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors. Nature 487, 505–509 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Bruennert, D. et al. Early in vivo changes of the transcriptome in Philadelphia chromosome-positive CD34+ cells from patients with chronic myelogenous leukaemia following imatinib therapy. Leukemia 23, 983–985 (2009).

    Article  CAS  PubMed  Google Scholar 

  24. Eferl, R. & Wagner, E.F. AP-1: a double-edged sword in tumorigenesis. Nat. Rev. Cancer 3, 859–868 (2003).

    Article  CAS  PubMed  Google Scholar 

  25. Lawan, A., Shi, H., Gatzke, F. & Bennett, A.M. Diversity and specificity of the mitogen-activated protein kinase phosphatase-1 functions. Cell. Mol. Life Sci. 70, 223–237 (2013).

    Article  CAS  PubMed  Google Scholar 

  26. Jeffrey, K.L., Camps, M., Rommel, C. & Mackay, C.R. Targeting dual-specificity phosphatases: manipulating MAP kinase signalling and immune responses. Nat. Rev. Drug Discov. 6, 391–403 (2007).

    Article  CAS  PubMed  Google Scholar 

  27. Brooks, S.A. & Blackshear, P.J. Tristetraprolin (TTP): interactions with mRNA and proteins, and current thoughts on mechanisms of action. Biochim. Biophys. Acta 1829, 666–679 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Dorfman, K. et al. Disruption of the erp/mkp-1 gene does not affect mouse development: normal MAP kinase activity in ERP/MKP-1-deficient fibroblasts. Oncogene 13, 925–931 (1996).

    CAS  PubMed  Google Scholar 

  29. Zhang, J. et al. c-fos regulates neuronal excitability and survival. Nat. Genet. 30, 416–420 (2002).

    Article  CAS  PubMed  Google Scholar 

  30. Zhao, C. et al. Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia. Nature 458, 776–779 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Ransone, L.J., Visvader, J., Wamsley, P. & Verma, I.M. Trans-dominant negative mutants of Fos and Jun. Proc. Natl. Acad. Sci. USA 87, 3806–3810 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Molina, G. et al. Zebrafish chemical screening reveals an inhibitor of Dusp6 that expands cardiac cell lineages. Nat. Chem. Biol. 5, 680–687 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Huang, T.S., Lee, S.C. & Lin, J.K. Suppression of c-Jun/AP-1 activation by an inhibitor of tumor promotion in mouse fibroblast cells. Proc. Natl. Acad. Sci. USA 88, 5292–5296 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Park, S., Lee, D.K. & Yang, C.H. Inhibition of fos-jun-DNA complex formation by dihydroguaiaretic acid and in vitro cytotoxic effects on cancer cells. Cancer Lett. 127, 23–28 (1998).

    Article  CAS  PubMed  Google Scholar 

  35. Padhye, S. et al. Fluorocurcumins as cyclooxygenase-2 inhibitor: molecular docking, pharmacokinetics and tissue distribution in mice. Pharm. Res. 26, 2438–2445 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Koschmieder, S. et al. Inducible chronic phase of myeloid leukemia with expansion of hematopoietic stem cells in a transgenic model of BCR-ABL leukemogenesis. Blood 105, 324–334 (2005).

    Article  CAS  PubMed  Google Scholar 

  37. Li, L. et al. Activation of p53 by SIRT1 inhibition enhances elimination of CML leukemia stem cells in combination with imatinib. Cancer Cell 21, 266–281 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Copland, M. et al. BMS-214662 potently induces apoptosis of chronic myeloid leukemia stem and progenitor cells and synergizes with tyrosine kinase inhibitors. Blood 111, 2843–2853 (2008).

    Article  CAS  PubMed  Google Scholar 

  39. Angel, P. & Karin, M. The role of Jun, Fos and the AP-1 complex in cell-proliferation and transformation. Biochim. Biophys. Acta 1072, 129–157 (1991).

    CAS  PubMed  Google Scholar 

  40. Owens, D.M. & Keyse, S.M. Differential regulation of MAP kinase signalling by dual-specificity protein phosphatases. Oncogene 26, 3203–3213 (2007).

    Article  CAS  PubMed  Google Scholar 

  41. Boutros, T., Chevet, E. & Metrakos, P. Mitogen-activated protein (MAP) kinase/MAP kinase phosphatase regulation: roles in cell growth, death, and cancer. Pharmacol. Rev. 60, 261–310 (2008).

    Article  CAS  PubMed  Google Scholar 

  42. Groom, L.A., Sneddon, A.A., Alessi, D.R., Dowd, S. & Keyse, S.M. Differential regulation of the MAP, SAP and RK/p38 kinases by Pyst1, a novel cytosolic dual-specificity phosphatase. EMBO J. 15, 3621–3632 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Fjeld, C.C., Rice, A.E., Kim, Y., Gee, K.R. & Denu, J.M. Mechanistic basis for catalytic activation of mitogen-activated protein kinase phosphatase 3 by extracellular signal-regulated kinase. J. Biol. Chem. 275, 6749–6757 (2000).

    Article  CAS  PubMed  Google Scholar 

  44. Zhao, Q. et al. MAP kinase phosphatase 1 controls innate immune responses and suppresses endotoxic shock. J. Exp. Med. 203, 131–140 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Hirsch, D.D. & Stork, P.J. Mitogen-activated protein kinase phosphatases inactivate stress-activated protein kinase pathways in vivo. J. Biol. Chem. 272, 4568–4575 (1997).

    Article  CAS  PubMed  Google Scholar 

  46. Young, P.R. et al. Pyridinyl imidazole inhibitors of p38 mitogen-activated protein kinase bind in the ATP site. J. Biol. Chem. 272, 12116–12121 (1997).

    Article  CAS  PubMed  Google Scholar 

  47. Bennett, B.L. et al. SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase. Proc. Natl. Acad. Sci. USA 98, 13681–13686 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Shojaee, S. et al. Erk negative feedback control enables pre-B cell transformation and represents a therapeutic target in acute lymphoblastic leukemia. Cancer Cell 28, 114–128 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Hrustanovic, G. et al. RAS-MAPK dependence underlies a rational polytherapy strategy in EML4-ALK-positive lung cancer. Nat. Med. 21, 1038–1047 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Zhang, B. et al. Altered microenvironmental regulation of leukemic and normal stem cells in chronic myelogenous leukemia. Cancer Cell 21, 577–592 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Reynaud, D. et al. IL-6 controls leukemic multipotent progenitor cell fate and contributes to chronic myelogenous leukemia development. Cancer Cell 20, 661–673 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Welner, R.S. et al. Treatment of chronic myelogenous leukemia by blocking cytokine alterations found in normal stem and progenitor cells. Cancer Cell 27, 671–681 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Roberts, K.G. et al. Genetic alterations activating kinase and cytokine receptor signaling in high-risk acute lymphoblastic leukemia. Cancer Cell 22, 153–166 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Druker, B.J. et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N. Engl. J. Med. 344, 1038–1042 (2001).

    Article  CAS  PubMed  Google Scholar 

  55. Chang, K.H. et al. Vav3 collaborates with p190-BCR-ABL in lymphoid progenitor leukemogenesis, proliferation, and survival. Blood 120, 800–811 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Bagger, F.O. et al. BloodSpot: a database of gene expression profiles and transcriptional programs for healthy and malignant haematopoiesis. Nucleic Acids Res. 44 D1, D917–D924 (2016).

    Article  CAS  PubMed  Google Scholar 

  57. Jørgensen, H.G., Allan, E.K., Jordanides, N.E., Mountford, J.C. & Holyoake, T.L. Nilotinib exerts equipotent antiproliferative effects to imatinib and does not induce apoptosis in CD34+ CML cells. Blood 109, 4016–4019 (2007).

    Article  CAS  PubMed  Google Scholar 

  58. Holyoake, T.L. & Vetrie, D. The chronic myeloid leukemia stem cell: stemming the tide of persistence. Blood https://dx.doi.org/10.1182/blood-2016-09-696013 (2017).

  59. Kesarwani, M. et al. Targeting substrate-site in Jak2 kinase prevents emergence of genetic resistance. Sci. Rep. 5, 14538 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Azam, M., Seeliger, M.A., Gray, N.S., Kuriyan, J. & Daley, G.Q. Activation of tyrosine kinases by mutation of the gatekeeper threonine. Nat. Struct. Mol. Biol. 15, 1109–1118 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Komurov, K., Dursun, S., Erdin, S. & Ram, P.T. NetWalker: a contextual network analysis tool for functional genomics. BMC Genomics 13, 282 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors are thankful to H. Singh and Y. Zheng for providing critical feedback on this study. We are thankful to G. Daley for providing the BaF3-BA cells and T. Reya for the MSCV-BCR-ABL-Ires-YFP constructs. We are thankful to M. Carroll for providing the patient samples from the CML blast crisis. This study was supported by grants to M.A. from the NCI (1RO1CA155091), Leukemia Research Foundation and V Foundation and from the NHLBI (R21HL114074-01).

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Authors and Affiliations

  1. Division of Experimental Hematology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA

    Meenu Kesarwani, Zachary Kincaid, Ahmed Gomaa, Erika Huber, Sara Rohrabaugh, Zain Siddiqui, Muhammad F Bouso, Kakajan Komurov, James C Mulloy, Jose A Cancelas, H Leighton Grimes & Mohammad Azam

  2. Department of Medicine, University of Cincinnati, Cincinnati, Ohio, USA

    Tahir Latif

  3. Department of Anesthesia and Critical Care, University of Chicago, Chicago, Illinois, USA

    Ming Xu

  4. Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA

    H Leighton Grimes

  5. Division of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA

    Mohammad Azam

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  1. Meenu Kesarwani
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Contributions

Experiments were conceived and designed by M.K. and M.A. Experiments were performed by M.K., Z.K., A.G., E.H., S.R, Z.S., M.F.B., T.L., M.X., J.C.M., J.A.C., and H.L.G. Bioinformatics analysis of microarrays and RNA-seq data were performed by M.K. and K.K. The manuscript was written by M.K. and M.A.

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Correspondence to Mohammad Azam.

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Kesarwani, M., Kincaid, Z., Gomaa, A. et al. Targeting c-FOS and DUSP1 abrogates intrinsic resistance to tyrosine-kinase inhibitor therapy in BCR-ABL-induced leukemia. Nat Med 23, 472–482 (2017). https://doi.org/10.1038/nm.4310

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