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Inhibition of MAPKinase pathway sensitizes thyroid cancer cells to ABT-737 induced apoptosis

Viswanath Gunda1, Kristopher A Sarosiek2, Eran Brauner1

  • 1Thyroid Cancer Research Laboratory, Endocrine Surgery Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Cancer Letters
|March 6, 2017
PubMed

Insights

Targeting Bcl2 family proteins and ERK pathway simultaneously can induce apoptosis in aggressive thyroid cancer. BH3-profiling can guide personalized, targeted therapies for better patient outcomes.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Bcl2 family proteins are crucial in thyroid cancer cell survival and resistance to apoptosis.
  • Papillary thyroid cancer (PTC) cells exhibit dependence on specific Bcl2 proteins like Bcl-xL, Bcl2, and Mcl-1 for survival.

Purpose of the Study:

  • To investigate the efficacy of combined targeting of Bcl2 family proteins and the ERK pathway in thyroid cancer.
  • To evaluate the potential of BH3-profiling and tumor mutational status for personalized thyroid cancer treatment.

Main Methods:

  • BH3-profiling was performed on seven primary PTC tumors and thyroid cancer cell lines.
  • Combination therapy using BH3 mimetic ABT-737 and ERK inhibitors (PLX4720, PD325901) was tested in vitro and in orthotopic mouse models.
  • Apoptosis levels, tumor size, and expression of pro- and anti-apoptotic proteins (Bim, Mcl-1) were assessed.

Main Results:

  • The triple drug combination significantly induced apoptosis in most tested thyroid cancer cell lines and reduced tumor size in mouse models.
  • Treatment increased pro-apoptotic protein Bim and decreased anti-apoptotic protein Mcl-1 expression.
  • BH3-profiling revealed differential dependence on Bcl2 family proteins in primary tumors and cell lines.

Conclusions:

  • Combined inhibition of Bcl2 family proteins and the ERK pathway is a promising strategy for aggressive thyroid cancer.
  • BH3-profiling combined with tumor mutational analysis can guide effective, personalized therapeutic approaches.
  • This approach holds potential for targeted treatment of aggressive thyroid cancer, improving patient outcomes.
Keywords:
ApoptosisBRAF(V600E) inhibitorBcl2 family proteinOrthotopic modelThyroid cancer

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