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Destabilizing RET in targeted treatment of thyroid cancers

M L Gild1, M Bullock1, C K Pon1

  • 1Cancer Genetics LaboratoryKolling Institute of Medical Research, Sydney, New South Wales, AustraliaDepartment of EndocrinologyRoyal North Shore Hospital, The University of Sydney, Sydney, New South Wales 2065, Australia.

Endocrine Connections
|November 18, 2015
PubMed

Insights

HSP90 inhibitor AUY922 effectively reduced growth and increased apoptosis in medullary and papillary thyroid cancer cells. This approach also enhanced radioactive iodine uptake in papillary thyroid cancer cells, suggesting a new treatment avenue.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Metastatic differentiated thyroid cancers (DTC) exhibit resistance to conventional chemotherapy.
  • Kinase inhibitors show promise for progressive DTC but often cause dose-limiting toxicities.
  • Heat Shock Protein 90 (HSP90) regulates key growth-mediating kinases like RET, implicated in thyroid cancer progression.

Purpose of the Study:

  • To investigate the efficacy of the HSP90 inhibitor AUY922 against RET-driven medullary thyroid cancer (MTC) and papillary thyroid cancer (PTC) cell lines.
  • To assess AUY922's impact on cancer cell growth, apoptosis, and radioactive iodine uptake in PTC.
  • To explore the underlying molecular mechanisms of AUY922's anti-cancer effects.

Main Methods:

  • Utilized MTC cell lines (TT, MZ-CRC-1) and a PTC cell line (TPC-1) harboring RET alterations.
  • Assessed cell viability using MTS assays and apoptosis via flow cytometry.
  • Analyzed signaling pathway inhibition (MAPK, mTOR, AKT) by western blot and measured radioiodine uptake using a gamma counter.

Main Results:

  • AUY922 treatment simultaneously inhibited MAPK and mTOR pathways, inducing significant apoptosis in both MTC cell lines (e.g., 78.7% reduction in TT cells at 1 μM).
  • In the PTC cell line, AUY922 inhibited growth and signaling targets, leading to a 2.84-fold increase in radioactive iodine uptake (P=0.015).
  • Western blot analysis confirmed the inhibition of pro-survival proteins like AKT, supporting apoptosis induction.

Conclusions:

  • AUY922 demonstrates significant in vitro anti-tumor activity against MTC and PTC cell lines, characterized by potent, dose-dependent apoptosis induction.
  • HSP90 inhibition with AUY922 enhances radioactive iodine uptake in PTC cells, a critical factor for targeted therapy.
  • HSP90 inhibition represents a promising therapeutic strategy for RET-driven, chemo-resistant thyroid cancers.
Keywords:
AUY922HSP90MAPKRETmTORthyroid cancer

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