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Elucidating mechanisms of sunitinib resistance in renal cancer: an integrated pathological-molecular analysis

Henriett Butz1,2, Qiang Ding1,2, Roy Nofech-Mozes1

  • 1Department of Laboratory Medicine, and The Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, ON, M5B 1W8, Canada.

Oncotarget
|February 14, 2018
PubMed

Insights

Sunitinib resistance in metastatic renal cell carcinoma is linked to tumor cells becoming migratory. Downregulated miR-1 and miR-663a target FRAS1 and MDGA1, offering potential therapeutic targets.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Metastatic renal cell carcinoma (mRCC) patients often develop resistance to sunitinib treatment.
  • Understanding the molecular mechanisms underlying sunitinib resistance is crucial for improving patient outcomes.

Purpose of the Study:

  • To investigate the role of microRNAs (miRNAs) in the development of sunitinib resistance in mRCC.
  • To identify potential therapeutic targets for overcoming sunitinib resistance.

Main Methods:

  • Development of in vivo xenograft and in vitro models of sunitinib resistance.
  • Comprehensive analysis of morphological, immunohistochemical, transcriptomic, and miRNome data using next-generation sequencing.
  • Bioinformatic analyses including pathway, BioFunction, and network analysis.
  • Validation of findings through in vitro functional assays.

Main Results:

  • Sunitinib resistance is associated with a phenotypic shift in tumor cells towards migration.
  • Downregulation of miR-1 and miR-663a was observed in resistant tumors.
  • miR-1 targets FRAS1 (Fraser Extracellular Matrix Complex Subunit 1) and miR-663a targets MDGA1 (MAM Domain Containing Glycosylphosphatidylinositol Anchor 1).
  • Knockdown of MDGA1 mimicked the effects of miR-1 and miR-663a restoration, reducing renal cancer cell migration and proliferation.

Conclusions:

  • Cell migration is a key adaptive mechanism for tumor survival during sunitinib resistance in mRCC.
  • The miR-1/FRAS1 and miR-663a/MDGA1 pathways are critical in mediating sunitinib resistance.
  • MDGA1, FRAS1, or their targeting miRNAs represent potential adjuvant therapeutic targets to inhibit cancer cell migration and prevent resistance and metastasis.
Keywords:
metastasismiRNAsrenal cell carcinomaresistancesunitinib

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