Skip to main content

Thank you for visiting nature.com. 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.

  • Opinion
  • Published:

Cancer revoked: oncogenes as therapeutic targets

Nature Reviews Cancer volume 3, pages 375–379 (2003)Cite this article

Abstract

Recent findings show that even the brief inactivation of a single oncogene might be sufficient to result in the sustained loss of a neoplastic phenotype. It is therefore possible that the targeted inactivation of oncogenes could be a specific and effective treatment for cancer. So why does oncogene inactivation cause tumour regression and will this be a generally successful approach for the treatment of human neoplasia?

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Possible outcomes following oncogene inactivation.
Figure 2: Oncogene inactivation might revoke tumorigenesis by changing the epigenetic programme of a cell.

Similar content being viewed by others

References

  1. Chin, L. et al. Essential role for oncogenic Ras in tumour maintenance. Nature 400, 468–472 (1999).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  4. Pelengaris, S., Littlewood, T., Khan, M., Elia, G. & Evan, G. 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 

  5. 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 

  6. Huettner, C. S., Zhang, P., Van Etten, R. A. & Tenen, D. G. Reversibility of acute B-cell leukaemia induced by BCR–ABL1. Nature Genet. 24, 57–60 (2000).

    Article  CAS  Google Scholar 

  7. D'Cruz, C. M. et al. c-MYC induces mammary tumorigenesis by means of a preferred pathway involving spontaneous Kras2 mutations. Nature Med. 7, 235–239 (2001).

    Article  CAS  Google Scholar 

  8. Fisher, G. H. et al. Induction and apoptotic regression of lung adenocarcinomas by regulation of a K-Ras transgene in the presence and absence of tumor suppressor genes. Genes Dev. 15, 3249–3262 (2001).

    Article  CAS  Google Scholar 

  9. Sawyers, C. L. Disabling Abl-perspectives on Abl kinase regulation and cancer therapeutics. Cancer Cell 1, 13–15 (2002).

    Article  CAS  Google Scholar 

  10. Sawyers, C. L. Finding the next Gleevec: FLT3 targeted kinase inhibitor therapy for acute myeloid leukemia. Cancer Cell 1, 413–415 (2002).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  12. Gossen, M. et al. Transcriptional activation by tetracyclines in mammalian cells. Science 268, 1766–1769 (1995).

    Article  CAS  Google Scholar 

  13. Kistner, A. et al. Doxycycline-mediated quantitative and tissue-specific control of gene expression in transgenic mice. Proc. Natl Acad. Sci. USA 93, 10933–10938 (1996).

    Article  CAS  Google Scholar 

  14. Karlsson, A. et al. Genomically complex lymphomas undergo sustained tumor regression upon MYC inactivation unless they acquire novel chromosomal translocations. Blood 101, 2797–2803.

  15. Ewald, D. et al. Time-sensitive reversal of hyperplasia in transgenic mice expressing SV40 T antigen. Science 273, 1384–1386 (1996).

    Article  CAS  Google Scholar 

  16. Felsher, D. W. & Bishop, J. M. Transient excess of MYC activity can elicit genomic instability and tumorigenesis. Proc. Natl Acad. Sci. USA 96, 3940–3944 (1999).

    Article  CAS  Google Scholar 

  17. Gunther, E. J. et al. Impact of p53 loss on reversal and recurrence of conditional Wnt-induced tumorigenesis. Genes Dev. 17, 488–501 (2003).

    Article  CAS  Google Scholar 

  18. Druker, B. J. et al. Efficacy and safety of a specific inhibitor of the BCR–ABL tyrosine kinase in chronic myeloid leukemia. N. Engl. J. Med. 344, 1031–1037 (2001).

    Article  CAS  Google Scholar 

  19. Kantarjian, H. et al. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N. Engl. J. Med. 346, 645–652 (2002).

    Article  CAS  Google Scholar 

  20. Talpaz, M. et al. Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: results of a phase 2 study. Blood 99, 1928–1937 (2002).

    Article  CAS  Google Scholar 

  21. Demetri, G. D. et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N. Engl. J. Med. 347, 472–480 (2002).

    Article  CAS  Google Scholar 

  22. Gorre, M. E. & Sawyers, C. L. Molecular mechanisms of resistance to STI571 in chronic myeloid leukemia. Curr. Opin. Hematol. 9, 303–307 (2002).

    Article  Google Scholar 

  23. Shah, N. P. et al. Multiple BCR–ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia. Cancer Cell 2, 117–125 (2002).

    Article  CAS  Google Scholar 

  24. Greaves, M. F. Differentiation-linked leukemogenesis in lymphocytes. Science 234, 697–704 (1986).

    Article  CAS  Google Scholar 

  25. Holtzer, H., Biehl, J., Yeoh, G., Meganathan, R. & Kaji, A. Effect of oncogenic virus on muscle differentiation. Proc. Natl Acad. Sci. USA 72, 4051–4055 (1975).

    Article  CAS  Google Scholar 

  26. Boettiger, D., Soltesz, R., Holtzer, H. & Pacifici, M. Infection of chick limb bud presumptive chondroblasts by a temperature-sensitive mutant of Rous sarcoma virus and the reversible inhibition of their terminal differentiation in culture. Mol. Cell. Biol. 3, 1518–1526 (1983).

    Article  CAS  Google Scholar 

  27. Esteller, M. et al. Cancer epigenetics and methylation. Science 297, 1807–1808; discussion 1807–1808 (2002).

    Article  Google Scholar 

  28. Rhee, I. et al. DNMT1 and DNMT3b cooperate to silence genes in human cancer cells. Nature 416, 552–556 (2002).

    Article  CAS  Google Scholar 

  29. Jang, M. et al. Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science 275, 218–220 (1997).

    Article  CAS  Google Scholar 

  30. Okamoto, A. et al. Mutations and altered expression of p16INK4 in human cancer. Proc. Natl Acad. Sci. USA 91, 11045–11049 (1994).

    Article  CAS  Google Scholar 

  31. Berman, D. M. et al. Medulloblastoma growth inhibition by hedgehog pathway blockade. Science 297, 1559–1561 (2002).

    Article  CAS  Google Scholar 

  32. Di Croce, L. et al. Methyltransferase recruitment and DNA hypermethylation of target promoters by an oncogenic transcription factor. Science 295, 1079–1082 (2002).

    Article  CAS  Google Scholar 

  33. Ogawa, H., Ishiguro, K., Gaubatz, S., Livingston, D. M. & Nakatani, Y. A complex with chromatin modifiers that occupies E2F- and Myc-responsive genes in G0 cells. Science 296, 1132–1136 (2002).

    Article  CAS  Google Scholar 

  34. Bakin, A. V. & Curran, T. Role of DNA 5-methylcytosine transferase in cell transformation by fos. Science 283, 387–390 (1999).

    Article  CAS  Google Scholar 

  35. Baudino, T. A. et al. c-Myc is essential for vasculogenesis and angiogenesis during development and tumor progression. Genes Dev. 16, 2530–2543 (2002).

    Article  CAS  Google Scholar 

  36. Huang, M. E. et al. Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia. Blood 72, 567–572 (1988).

    CAS  PubMed  Google Scholar 

  37. Sanz, M. A., Martin, G. & Diaz-Mediavilla, J. All-trans-retinoic acid in acute promyelocytic leukemia. N. Engl. J. Med. 338, 393–394 (1998).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Thank you to the members of my laboratory for a critical reading of the manuscript, and to H. Varmus and G. Klein for kindly bringing relevant literature to my attention. D.W.F. is supported by grants from the National Institutes of Health, the Lymphoma Research Foundation, the Elsa Pardee Foundation and the Esther Ehrman Lazard Faculty Scholar Award.

Author information

Authors and Affiliations

  1. the Division of Oncology, Departments of Medicine and Pathology, Stanford University, 269 Campus Drive, CCSR 1105, Stanford, 94305-5151, California, USA

    Dean W. Felsher

Authors
  1. Dean W. Felsher
    View author publications

    You can also search for this author in PubMed Google Scholar

Related links

Related links

DATABASES

Cancer.gov

bone cancer

chronic myelogenous leukaemia

leukaemia

lung cancer

LocusLink

ABL

BCL-X L

BCR

CDKN2A

ERT

LMYC

MYC

NMYC

p53

PML

RARa

RAS

SRC

Wnt1

FURTHER INFORMATION

Dean Felsher's lab

Rights and permissions

Reprints and permissions

About this article

Cite this article

Felsher, D. Cancer revoked: oncogenes as therapeutic targets. Nat Rev Cancer 3, 375–379 (2003). https://doi.org/10.1038/nrc1070

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc1070

This article is cited by

Search

Advanced search

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