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Gene expression and linkage analysis implicate CBLB as a mediator of rituximab resistance

The Pharmacogenomics Journal volume 18, pages 467–473 (2018)Cite this article

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Abstract

Elucidating resistance mechanisms for therapeutic monoclonal antibodies (MAbs) is challenging, because they are difficult to study in non-human models. We therefore developed a strategy to genetically map in vitro drug sensitivity, identifying genes that alter responsiveness to rituximab, a therapeutic anti-CD20 MAb that provides significant benefit to patients with B-cell malignancies. We discovered novel loci with genome-wide mapping analyses and functionally validated one of these genes, CBLB, which causes rituximab resistance when knocked down in lymphoma cells. This study demonstrates the utility of genome-wide mapping to discover novel biological mechanisms of potential clinical advantage.

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Acknowledgements

This work was supported a Mentored Research Scholar Grant in Applied and Clinical Research (MSRG-12-086-01-TBG) from the American Cancer Society, an R01 Grant (5R01 CA185372) from the National Cancer Institute to KLR and an RO1 (5R01CA161608) from the National Cancer Institute to AMR and HLM.

Author information

Author notes

  1. J Jack and G W Small: These two authors contributed equally to this work.

  2. A A Motsinger-Reif and K L Richards: These two authors contributed equally to this work.

Authors and Affiliations

  1. Department of Statistics, North Carolina State University, Raleigh, NC, USA

    J Jack & A A Motsinger-Reif

  2. Bioinformatics Research Center, North Carolina State University, Raleigh, NC, USA

    J Jack & A A Motsinger-Reif

  3. Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    G W Small

  4. Q2 Solutions – EA Genomics, A Quintiles Quest Joint Venture, Morrisville, NC, USA

    C C Brown

  5. Center for Pharmacogenomics and Individualized Therapy, University of North Carolina, Chapel Hill, NC, USA

    T M Havener

  6. DeBartolo Family Personalized Medicine Institute, Moffitt Cancer Center, Tampa, Florida, USA

    H L McLeod

  7. Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA

    K L Richards

  8. Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY, USA

    K L Richards

Authors
  1. J Jack
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  4. T M Havener
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Corresponding authors

Correspondence to A A Motsinger-Reif or K L Richards.

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Jack, J., Small, G., Brown, C. et al. Gene expression and linkage analysis implicate CBLB as a mediator of rituximab resistance. Pharmacogenomics J 18, 467–473 (2018). https://doi.org/10.1038/tpj.2017.41

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  • DOI: https://doi.org/10.1038/tpj.2017.41

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