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Assessment of Resistance to Tyrosine Kinase Inhibitors by an Interrogation of Signal Transduction Pathways by Antibody Arrays
07:42

Assessment of Resistance to Tyrosine Kinase Inhibitors by an Interrogation of Signal Transduction Pathways by Antibody Arrays

Published on: September 19, 2018

Inhibition of RET tyrosine kinase by SU5416

Luca Mologni1, Elisa Sala, Sara Cazzaniga

  • 1Department of Clinical Medicine, Prevention and Biotechnology, University of Milan-Bicocca, Monza, Italy. luca.mologni@unimib.it

Journal of Molecular Endocrinology
|October 13, 2006
PubMed

Insights

SU5416 effectively inhibits rearranged during transfection (RET) in thyroid cancer cells, halting proliferation. However, specific mutations like MEN2 confer resistance, suggesting tailored therapeutic approaches for RET-driven neoplasms.

Area of Science:

  • Molecular Oncology
  • Signal Transduction
  • Drug Discovery

Background:

  • Thyroid neoplasia often involves mutations in the rearranged during transfection (RET) proto-oncogene, leading to hyperactive RET kinase signaling.
  • Targeting RET-mediated signaling presents a potential therapeutic strategy for RET-driven thyroid cancers.
  • SU5416 is an established inhibitor of several receptor tyrosine kinases, including vascular endothelial cell growth factor receptor, c-Kit, and FLT-3.

Purpose of the Study:

  • To investigate the efficacy of SU5416 as a RET kinase inhibitor in thyroid cancer models.
  • To elucidate the signaling pathways affected by SU5416 in RET-driven cells.
  • To assess the impact of specific RET mutations on SU5416 sensitivity.

Main Methods:

  • Cell-free and cellular assays were employed to evaluate SU5416's inhibitory activity against RET.
  • Proliferation assays were conducted on cells transfected with oncogenic RET or expressing RET/PTC1.
  • Western blotting was used to analyze the inhibition of extracellular signal regulated kinase (ERK) and JNK pathways.
  • Molecular docking was utilized to explore resistance mechanisms associated with MEN2 mutations.
  • Kinase profiling assessed SU5416's activity against a panel of 52 kinases.

Main Results:

  • SU5416 demonstrated potent inhibition of RET kinase activity in both cell-free and cellular settings.
  • SU5416 induced proliferation arrest in papillary thyroid carcinoma (PTC) cells with oncogenic RET, but not in RET-negative cells.
  • Inhibition of RET-mediated signaling through the ERK and JNK pathways was observed.
  • A naturally occurring MEN2 mutation at codon 804 conferred resistance to SU5416, unlike the related compound SU4984.
  • Molecular docking provided insights into the differential sensitivity conferred by the MEN2 mutation.

Conclusions:

  • SU5416 is an effective inhibitor of RET kinase and demonstrates anti-proliferative effects in RET-driven thyroid cancer cells.
  • RET signaling pathways, including ERK and JNK, are targeted by SU5416.
  • Specific RET mutations, such as the MEN2 codon 804 variant, can lead to resistance to SU5416, highlighting the need for mutation-specific therapies.

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