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.

  • Letter to the Editor
  • Published:

The dual PI3K/mTOR inhibitor, NVP-BEZ235, is efficacious against follicular lymphoma

Leukemia volume 24, pages 1781–1784 (2010)Cite this article

Subjects

Follicular lymphoma (FL) is one of the most common forms of low-grade non-Hodgkin lymphoma in the Western hemisphere. It usually follows an indolent course. However, 25–60% of cases may transform to aggressive diffuse large B cell lymphomas. FLs are characterized by the t(14;18)(q32;q21) translocation, which results in the overexpression of a chimerical bcl-2/IgH transcript in FL cells. Overexpression of bcl-2 provides a constitutive survival signal for FL. The acquisition of additional mutations in genes, such as p53, leads to FL transformation to diffuse large B cell lymphomas. Although FL is sensitive to some chemotherapeutic agents, relapse is common and transformation to diffuse large B cell lymphomas is considered incurable with conventional chemotherapy. Hence, novel therapeutic agents are urgently needed to improve patient outcomes.

The PI3K/Akt/mTOR pathway has a critical role in cell survival and proliferation, and is often activated in many types of cancer. PI3K is activated upon growth factor binding to their cognate receptors. Activated PI3K leads to the activation of PI3K-dependent kinase, which phosphorylates and activates Akt.1 Phosphorylation of Akt at both serine 473 and threonine 308 is required for full activation.

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

Relevant articles

Open Access articles citing this article.

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
Figure 2

References

  1. Manning BD, Cantley LC . AKT/PKB signaling: navigating downstream. Cell 2007; 129: 1261–1274.

    Article  CAS  Google Scholar 

  2. Zha H, Raffeld M, Charboneau L, Pittaluga S, Kwak LW, Petricoin III E et al. Similarities of prosurvival signals in Bcl-2-positive and Bcl-2-negative follicular lymphomas identified by reverse phase protein microarray. Lab Invest 2004; 84: 235–244.

    Article  CAS  Google Scholar 

  3. Gulmann C, Espina V, Petricoin III E, Longo DL, Santi M, Knutsen T et al. Proteomic analysis of apoptotic pathways reveals prognostic factors in follicular lymphoma. Clin Cancer Res 2005; 11: 5847–5855.

    Article  CAS  Google Scholar 

  4. Ackler S, Xiao Y, Mitten MJ, Foster K, Oleksijew A, Refici M et al. ABT-263 and rapamycin act cooperatively to kill lymphoma cells in vitro and in vivo. Mol Cancer Ther 2008; 7: 3265–3274.

    Article  CAS  Google Scholar 

  5. Leseux L, Hamdi SM, Al Saati T, Capilla F, Recher C, Laurent G et al. Syk-dependent mTOR activation in follicular lymphoma cells. Blood 2006; 108: 4156–4162.

    Article  CAS  Google Scholar 

  6. Jacinto E, Loewith R, Schmidt A, Lin S, Ruegg MA, Hall A et al. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol 2004; 6: 1122–1128.

    Article  CAS  Google Scholar 

  7. Sin SH, Roy D, Wang L, Staudt MR, Fakhari FD, Patel DD et al. Rapamycin is efficacious against primary effusion lymphoma (PEL) cell lines in vivo by inhibiting autocrine signaling. Blood 2007; 109: 2165–2173.

    Article  CAS  Google Scholar 

  8. Shringarpure R, Catley L, Bhole D, Burger R, Podar K, Tai YT et al. Gene expression analysis of B-lymphoma cells resistant and sensitive to bortezomib. Br J Haematol 2006; 134: 145–156.

    Article  CAS  Google Scholar 

  9. 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 

  10. Gibbons JJ, Abraham RT, Yu K . Mammalian target of rapamycin: discovery of rapamycin reveals a signaling pathway important for normal and cancer cell growth. Semin Oncol 2009; 36 (Suppl 3): S3–S17.

    Article  CAS  Google Scholar 

  11. Dubrovska A, Kim S, Salamone RJ, Walker JR, Maira SM, Garcia-Echeverria C et al. The role of PTEN/Akt/PI3K signaling in the maintenance and viability of prostate cancer stem-like cell populations. Proc Natl Acad Sci USA 2009; 106: 268–273.

    Article  CAS  Google Scholar 

  12. Elenitoba-Johnson KS, Jenson SD, Abbott RT, Palais RA, Bohling SD, Lin Z et al. Involvement of multiple signaling pathways in follicular lymphoma transformation: p38-mitogen-activated protein kinase as a target for therapy. Proc Natl Acad Sci USA 2003; 100: 7259–7264.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by NIH grant RO1-CA096500 and UCRF funding to BD, and funding from the Leukemia and Lymphoma society (6021) and the AIDS malignancy consortium to DD. BD is a Leukemia and Lymphoma Society Scholar and a Burroughs Wellcome Fund Investigator in Infectious Disease. We acknowledge Novartis for providing us with NVP-BEZ235. We thank Charlene Ross and the Animal Studies core for their help. We thank Drs Thomas Shea and Kristy Richards as well as members of the Damania and Dittmer labs for helpful discussions.

Author information

Authors and Affiliations

  1. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    P M Bhende, S I Park, D P Dittmer & B Damania

  2. Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    P M Bhende, S I Park, D P Dittmer & B Damania

  3. Department of Pathology, University of Michigan, Ann Arbor, MI, USA

    M S Lim

Authors
  1. P M Bhende
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S I Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M S Lim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. D P Dittmer
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. B Damania
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to B Damania.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bhende, P., Park, S., Lim, M. et al. The dual PI3K/mTOR inhibitor, NVP-BEZ235, is efficacious against follicular lymphoma. Leukemia 24, 1781–1784 (2010). https://doi.org/10.1038/leu.2010.154

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2010.154

This article is cited by

Search

Advanced search

Quick links