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Loss of DAB2IP in RCC cells enhances their growth and resistance to mTOR-targeted therapies

Oncogene volume 35, pages 4663–4674 (2016)Cite this article

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Abstract

Targeted therapies using small-molecule inhibitors (SMIs) are commonly used in metastatic renal cell cancer (mRCC) patients; patients often develop drug resistance and eventually succumb to disease. Currently, understanding of mechanisms leading to SMIs resistance and any identifiable predictive marker(s) are still lacking. We discovered that DAB2IP, a novel Ras-GTPase-activating protein, was frequently epigenetically silenced in RCC, and DAB2IP loss was correlated with the overall survival of RCC patients. Loss of DAB2IP in RCC cells enhances their sensitivities to growth factor stimulation and resistances to SMI (such as mammalian target of rapamycin (mTOR) inhibitors). Mechanistically, loss of DAB2IP results in the activation of extracellular signal–regulated kinase/RSK1 and phosphoinositide-3 kinase/mTOR pathway, which synergizes the induction of hypoxia-inducible factor (HIF)-2α expression. Consequently, elevated HIF-2α suppresses p21/WAF1 expression that is associated with resistance to mTOR inhibitors. Thus combinatorial targeting both pathways resulted in a synergistic tumor inhibition. DAB2IP appears to be a new prognostic/predictive marker for mRCC patients, and its function provides a new insight into the molecular mechanisms of drug resistance to mTOR inhibitors, which also can be used to develop new strategies to overcome drug-resistant mRCC.

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Acknowledgements

We thank John Santoyo for editorial assistance. This work was supported in part by Jean H and John T Walter, Jr, Endowment for Research in Urologic Oncology (to J-TH), the National Natural Science Foundation of China (NSFC 81202014 to KW) and the Fundamental Research Funds for the Central Universities in China (to KW).

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Author notes

  1. J Zhou, J Luo and K Wu: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Urology, First Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an, China

    J Zhou, K Wu, Y Du, B Wang, D Wu & D He

  2. Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA

    J Zhou, E-j Yun, R-C Pong, C Authement, E Hernandez, V Margulis, Y Lotan & J-T Hsieh

  3. Department of Urology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China

    J Luo

  4. Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA

    P Kapur

  5. Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA

    J Yang & G Xiao

  6. Division of Urology, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Republic of China, Taiwan

    T-L Cha

  7. Department of Urology, China Medical University Hospital, Taichung, Republic of China, Taiwan

    H-C Wu

  8. Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA

    J Brugarolas

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  1. J Zhou
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Correspondence to D He or J-T Hsieh.

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Zhou, J., Luo, J., Wu, K. et al. Loss of DAB2IP in RCC cells enhances their growth and resistance to mTOR-targeted therapies. Oncogene 35, 4663–4674 (2016). https://doi.org/10.1038/onc.2016.4

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