Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Modelling Myc inhibition as a cancer therapy


Myc is a pleiotropic basic helix–loop–helix leucine zipper transcription factor that coordinates expression of the diverse intracellular and extracellular programs that together are necessary for growth and expansion of somatic cells1. In principle, this makes inhibition of Myc an attractive pharmacological approach for treating diverse types of cancer. However, enthusiasm has been muted by lack of direct evidence that Myc inhibition would be therapeutically efficacious, concerns that it would induce serious side effects by inhibiting proliferation of normal tissues, and practical difficulties in designing Myc inhibitory drugs. We have modelled genetically both the therapeutic impact and the side effects of systemic Myc inhibition in a preclinical mouse model of Ras-induced lung adenocarcinoma by reversible, systemic expression of a dominant-interfering Myc mutant. We show that Myc inhibition triggers rapid regression of incipient and established lung tumours, defining an unexpected role for endogenous Myc function in the maintenance of Ras-dependent tumours in vivo. Systemic Myc inhibition also exerts profound effects on normal regenerating tissues. However, these effects are well tolerated over extended periods and rapidly and completely reversible. Our data demonstrate the feasibility of targeting Myc, a common downstream conduit for many oncogenic signals, as an effective, efficient and tumour-specific cancer therapy.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Endogenous Myc function is required for formation and maintenance of early-stage Kras-induced lung hyperplasias/adenomas.
Figure 2: Myc inhibition elicits regression of established lung tumours.
Figure 3: Inhibition of endogenous Myc suppresses proliferation in skin, testis and GI tract.
Figure 4: The degenerative phenotypes induced by systemic Myc inhibition are rapidly and completely reversible on restoration of Myc function.

Similar content being viewed by others


  1. Oster, S. K., Ho, C. S., Soucie, E. L. & Penn, L. Z. The myc oncogene: MarvelouslY Complex. Adv. Cancer Res. 84, 81–154 (2002)

    Article  CAS  Google Scholar 

  2. Arvanitis, C. & Felsher, D. W. Conditionally MYC: insights from novel transgenic models. Cancer Lett. 226, 95–99 (2005)

    Article  CAS  Google Scholar 

  3. Felsher, D. W. & Bishop, J. M. Reversible tumorigenesis by MYC in hematopoietic lineages. Mol. Cell 4, 199–207 (1999)

    Article  CAS  Google Scholar 

  4. Flores, I. et al. Defining the temporal requirements for Myc in the progression and maintenance of skin neoplasia. Oncogene 23, 5923–5930 (2004)

    Article  CAS  Google Scholar 

  5. Jain, M. et al. Sustained loss of a neoplastic phenotype by brief inactivation of MYC. Science 297, 102–104 (2002)

    Article  ADS  CAS  Google Scholar 

  6. Pelengaris, S., Khan, M. & Evan, G. I. Suppression of Myc-induced apoptosis in beta cells exposes multiple oncogenic properties of Myc and triggers carcinogenic progression. Cell 109, 321–334 (2002)

    Article  CAS  Google Scholar 

  7. Pelengaris, S. et al. Reversible activation of c-Myc in skin: induction of a complex neoplastic phenotype by a single oncogenic lesion. Mol. Cell 3, 565–577 (1999)

    Article  CAS  Google Scholar 

  8. Amati, B., Littlewood, T. D., Evan, G. I. & Land, H. The c-Myc protein induces cell cycle progression and apoptosis through dimerization with Max. EMBO J. 12, 5083–5087 (1993)

    Article  CAS  Google Scholar 

  9. Ferre-D’Amare, A. R., Prendergast, G. C., Ziff, E. B. & Burley, S. K. Recognition by Max of its cognate DNA through a dimeric b/HLH/Z domain. Nature 363, 38–45 (1993)

    Article  ADS  Google Scholar 

  10. Nair, S. K. & Burley, S. K. Structural aspects of interactions within the Myc/Max/Mad network. Curr. Top. Microbiol. Immunol. 302, 123–143 (2006)

    CAS  PubMed  Google Scholar 

  11. Amati, B. et al. Oncogenic activity of the c-Myc protein requires dimerisation with Max. Cell 72, 233–245 (1993)

    Article  CAS  Google Scholar 

  12. Chen, J. et al. Effects of the MYC oncogene antagonist, MAD, on proliferation, cell cycling and the malignant phenotype of human brain tumour cells. Nature Med. 1, 638–643 (1995)

    Article  CAS  Google Scholar 

  13. Prochownik, E. V. c-Myc as a therapeutic target in cancer. Expert Rev. Anticancer Ther. 4, 289–302 (2004)

    Article  CAS  Google Scholar 

  14. Soucek, L. et al. Design and properties of a Myc derivative that efficiently homodimerizes. Oncogene 17, 2463–2472 (1998)

    Article  CAS  Google Scholar 

  15. Soucek, L. et al. Omomyc, a potential Myc dominant negative, enhances Myc-induced apoptosis. Cancer Res. 62, 3507–3510 (2002)

    CAS  PubMed  Google Scholar 

  16. Soucek, L., Nasi, S. & Evan, G. I. Omomyc expression in skin prevents Myc-induced papillomatosis. Cell Death Differ. 11, 1038–1045 (2004)

    Article  CAS  Google Scholar 

  17. Baskar, J. F. et al. The enhancer domain of the human cytomegalovirus major immediate-early promoter determines cell type-specific expression in transgenic mice. J. Virol. 70, 3207–3214 (1996)

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Furth, P. A. et al. The variability in activity of the universally expressed human cytomegalovirus immediate early gene 1 enhancer/promoter in transgenic mice. Nucleic Acids Res. 19, 6205–6208 (1991)

    Article  CAS  Google Scholar 

  19. Kothary, R. et al. Unusual cell specific expression of a major human cytomegalovirus immediate early gene promoter-lacZ hybrid gene in transgenic mouse embryos. Mech. Dev. 35, 25–31 (1991)

    Article  CAS  Google Scholar 

  20. Zhan, Y., Brady, J. L., Johnston, A. M. & Lew, A. M. Predominant transgene expression in exocrine pancreas directed by the CMV promoter. DNA Cell Biol. 19, 639–645 (2000)

    Article  CAS  Google Scholar 

  21. Jackson, E. L. et al. The differential effects of mutant p53 alleles on advanced murine lung cancer. Cancer Res. 65, 10280–10288 (2005)

    Article  CAS  Google Scholar 

  22. Jackson, E. L. et al. Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras. Genes Dev. 15, 3243–3248 (2001)

    Article  CAS  Google Scholar 

  23. Sweet-Cordero, A. et al. An oncogenic KRAS2 expression signature identified by cross-species gene-expression analysis. Nature Genet. 37, 48–55 (2005)

    Article  CAS  Google Scholar 

  24. Okabe, M. et al. ‘Green mice’ as a source of ubiquitous green cells. FEBS Lett. 407, 313–319 (1997)

    Article  CAS  Google Scholar 

  25. Sarin, K. Y. et al. Conditional telomerase induction causes proliferation of hair follicle stem cells. Nature 436, 1048–1052 (2005)

    Article  ADS  CAS  Google Scholar 

  26. Sawamura, D. et al. Promoter/enhancer cassettes for keratinocyte gene therapy. J. Invest. Dermatol. 112, 828–830 (1999)

    Article  CAS  Google Scholar 

  27. Wright, D. E. et al. Cyclophosphamide/granulocyte colony-stimulating factor causes selective mobilization of bone marrow hematopoietic stem cells into the blood after M phase of the cell cycle. Blood 97, 2278–2285 (2001)

    Article  CAS  Google Scholar 

  28. Korinek, V. et al. Depletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4. Nature Genet. 19, 379–383 (1998)

    Article  CAS  Google Scholar 

  29. Murphy, M. J., Wilson, A. & Trumpp, A. More than just proliferation: Myc function in stem cells. Trends Cell Biol. 15, 128–137 (2005)

    Article  CAS  Google Scholar 

  30. Evan, G. I. Can’t kick that oncogene habit. Cancer Cell 10, 345–347 (2006)

    Article  CAS  Google Scholar 

Download references


We thank T. Jacks and S. Artandi for their gifts of LSL-KrasG12D and β-actin-rtTA+ mice, respectively. We thank F. Rostker for technical assistance and Y. Yaron and L. Johnson for advice on the LSL-KrasG12D model and adenovirus inhalation. We thank our laboratory colleagues for their comments and feedback. This study was supported by grant 2R01 CA98018 from the National Cancer Institute (to G.I.E.). S.N. acknowledges support from AIRC, ASI, CNR, MIUR FIRB and FIRS. C.P.M. is a Leukemia and Lymphoma Society Fellow. J.W. acknowledges support from Human Frontier Science Program. This paper is dedicated to the memory of Judah Folkman.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Gerard I. Evan.

Supplementary information

Supplementary Information

The file contains Supplementary Figures and Legends 1-4; Supplementary Tables 1-3. Supplementary Figure 1 represents quantitation of Omomyc and c-Myc expression in mouse tissues; Supplementary Figure 2 shows no influence of long-term systemic Omomyc expression on mouse weight; Supplementary. Figure 3 demonstrates that systemic Omomyc expression suppresses hair re-growth; Supplementary Figure 4 shows that induction of Omomyc in TRE-Omomyc; β-actin-rtTA mice recapitulates the intestinal and skin phenotypes of Doxycylin treated TREOmomyc;CMVrtTA mice and, additionally, elicits increased extramedullary hematopoiesis in spleen. Supplementary Table 1 shows that long-term systemic Omomyc expression has no significant impact on blood chemistry; Supplementary Table 2 includes blood counts showing that Omomyc expression causes transient anemia; Supplementary Table 3 includes detailed list of number and genotype of mice used for the experiments. (PDF 14691 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Soucek, L., Whitfield, J., Martins, C. et al. Modelling Myc inhibition as a cancer therapy. Nature 455, 679–683 (2008).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing