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

Cancer Lett. 2017 Jun 1:395:1-10. doi: 10.1016/j.canlet.2017.02.028. Epub 2017 Mar 1.

Abstract

Bcl2 family proteins play an important role in the resistance of thyroid cancer cells to apoptosis induced by chemotherapeutic drugs and targeted therapies. BH3-profiling of seven fresh primary papillary thyroid cancer (PTC) tumors showed dependence for survival on Bcl-xL (2/7), Bcl2 (2/7), and Mcl-1 (2/7), while the majority of thyroid cell lines were mainly dependent on Bcl-xL. Targeting Bcl2 family proteins with the BH3 mimetic, ABT-737, while simultaneously inhibiting ERK pathway proteins with PLX4720 and PD325901 was shown to induce significantly high apoptosis in the majority of cell lines (8505c, SW1736, HTh7, BCPAP) and moderate apoptosis in the TPC-1 cell line. In orthotopic thyroid cancer mouse models of 8505c and BCPAP, treatment with the triple drug combination reduced the size of the tumors and showed significantly higher numbers of cells undergoing apoptosis. This treatment increased the expression of pro-apoptotic protein Bim, while decreasing anti-apoptotic protein Mcl-1. Our results suggest that analyzing the results of BH3-profiling along with the mutational status of tumor can reveal an effective therapy for targeted, personalized treatment of aggressive thyroid cancer.

Keywords: Apoptosis; BRAF(V600E) inhibitor; Bcl2 family protein; Orthotopic model; Thyroid cancer.

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Benzamides / pharmacology
  • Biphenyl Compounds / pharmacology*
  • Cell Line, Tumor
  • Diphenylamine / analogs & derivatives
  • Diphenylamine / pharmacology
  • Female
  • Humans
  • Indoles / pharmacology
  • MAP Kinase Signaling System / physiology*
  • Mice
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Nitrophenols / pharmacology*
  • Piperazines / pharmacology
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-bcl-2 / physiology
  • Sulfonamides / pharmacology*
  • Thyroid Neoplasms / drug therapy*
  • Thyroid Neoplasms / pathology
  • bcl-X Protein / physiology

Substances

  • ABT-737
  • Benzamides
  • Biphenyl Compounds
  • Indoles
  • Nitrophenols
  • PLX 4720
  • Piperazines
  • Proto-Oncogene Proteins c-bcl-2
  • Sulfonamides
  • bcl-X Protein
  • mirdametinib
  • Diphenylamine
  • Mitogen-Activated Protein Kinases