Accelerated tumor growth mediated by sublytic levels of antibody-induced complement activation is associated with activation of the PI3K/AKT survival pathway Journal Article


Authors: Wu, X.; Ragupathi, G.; Panageas, K.; Hong, F.; Livingston, P. O.
Article Title: Accelerated tumor growth mediated by sublytic levels of antibody-induced complement activation is associated with activation of the PI3K/AKT survival pathway
Abstract: Purpose: We addressed the possibility that low levels of tumor cell-bound antibodies targeting gangliosides might accelerate tumor growth. Experimental Design: To test this hypothesis, we treated mice with a range of monoclonal antibody (mAb) doses against GM2, GD2, GD3, and CD20 after challenge with tumors expressing these antigens and tested the activity of the same mAbs in vitro. We also explored the mechanisms behind the complementmediated tumor growth acceleration that we observed and an approach to overcome it. Results: Serologically detectable levels of IgM-mAb against GM2 are able to delay or prevent tumor growth of high GM2 expressing cell lines both in vitro and in a SCID mouse model, whereas very low levels of this mAb resulted in slight but consistent acceleration of tumor growth in both settings. Surprisingly, this is not restricted to IgM mAb targeting GM2 but consistent against an IgG mAb targeting GD3 as well. These findings were mirrored by in vitro studies with antibodies against these antigens as well as GD2 and CD20 (with Rituxan), and shown to be complement-dependent in all cases. Complement-mediated accelerated growth of cultured tumor cell lines initiated by low mAb levels was associated with activation of the phosphoinositide 3-kinase (PI3K)/AKT survival pathway and significantly elevated levels of both p-AKT and p-PRAS40. This complement-mediated PI3K activation and accelerated tumor growth in vitro and in vivo are eliminated by PI3K inhibitors NVP-BEZ235 and Wortmannin. These PI3K inhibitors also significantly increased efficacy of high doses of these four mAbs. Conclusion: Our findings suggest that manipulation of the PI3K/AKT pathway and its signaling network can significantly increase the potency of passively administered mAbs and vaccine-induced antibodies targeting a variety of tumor cell surface antigens. ©2013 AACR.
Journal Title: Clinical Cancer Research
Volume: 19
Issue: 17
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2013-09-01
Start Page: 4728
End Page: 4739
Language: English
DOI: 10.1158/1078-0432.ccr-13-0088
PROVIDER: scopus
PMCID: PMC3769223
PUBMED: 23833306
DOI/URL:
Notes: --- - "Export Date: 1 October 2013" - "CODEN: CCREF" - "Source: Scopus"
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MSK Authors
  1. Feng Hong
    10 Hong
  2. Govindaswami Ragupathi
    140 Ragupathi
  3. Katherine S Panageas
    443 Panageas
  4. Xiaohong Wu
    6 Wu