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A Semi-Quantitative Drug Affinity Responsive Target Stability DARTS assay for studying Rapamycin/mTOR interaction
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Loss of DAB2IP in RCC cells enhances their growth and resistance to mTOR-targeted therapies

J Zhou1,2, J Luo3, K Wu1

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

Oncogene
|February 16, 2016
PubMed

Insights

Loss of DAB2IP protein in renal cell cancer leads to resistance against targeted therapies. Restoring DAB2IP function or targeting related pathways may overcome drug resistance in metastatic renal cell cancer (mRCC).

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Metastatic renal cell cancer (mRCC) patients treated with small-molecule inhibitors (SMIs) often develop drug resistance.
  • Mechanisms of SMI resistance and predictive markers for mRCC remain poorly understood.

Purpose of the Study:

  • To investigate the role of DAB2IP in the development of SMI resistance in mRCC.
  • To identify DAB2IP as a potential prognostic/predictive marker and therapeutic target for mRCC.

Main Methods:

  • Analysis of DAB2IP epigenetic silencing in RCC.
  • Assessment of DAB2IP loss effects on cellular sensitivity to growth factors and SMIs.
  • Investigation of signaling pathways involved in DAB2IP-mediated drug resistance, including mTOR and HIF-2α.
  • Evaluation of combination therapy targeting identified pathways.

Main Results:

  • DAB2IP was frequently epigenetically silenced in RCC, correlating with poor patient survival.
  • Loss of DAB2IP enhanced sensitivity to growth factors and resistance to mTOR inhibitors.
  • DAB2IP loss activated the ERK/RSK1 and PI3K/mTOR pathways, increasing HIF-2α expression.
  • Elevated HIF-2α suppressed p21/WAF1, contributing to mTOR inhibitor resistance.
  • Combined targeting of these pathways synergistically inhibited tumor growth.

Conclusions:

  • DAB2IP is a novel prognostic/predictive marker for mRCC.
  • DAB2IP loss contributes to mTOR inhibitor resistance via HIF-2α activation.
  • Targeting DAB2IP or related pathways offers a new strategy to overcome drug resistance in mRCC.

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