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Trametinib downregulates survivin expression in RB1-positive KRAS-mutant lung adenocarcinoma cells

Toshiyuki Sumi1, Sachie Hirai2, Miki Yamaguchi2

  • 1Department of Molecular Medicine, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan; Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, Sapporo, Japan.

Biochemical and Biophysical Research Communications
|May 5, 2018
PubMed

Insights

Trametinib effectively targets KRAS-mutant lung adenocarcinomas by suppressing survivin in RB1-positive cells. However, RB1-negative tumors develop resistance, highlighting RB1 status as a key biomarker for treatment efficacy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • High survivin expression in KRAS-mutant lung adenocarcinomas correlates with poor patient prognosis.
  • Survivin is a potential therapeutic target for lung adenocarcinoma treatment.

Purpose of the Study:

  • To investigate the mechanism of trametinib-induced survivin downregulation in KRAS-mutant lung adenocarcinoma.
  • To determine the role of RB1 status in mediating trametinib's efficacy and resistance.

Main Methods:

  • Utilized RB1-positive (H358, H441) and RB1-negative (H2009) KRAS-mutant lung adenocarcinoma cell lines.
  • Treated cells with trametinib (MEK inhibitor) and assessed survivin, p21, and RB1 phosphorylation levels.
  • Performed p21 and RB1 knockdown experiments to elucidate their role in survivin suppression.
  • Developed and analyzed trametinib-resistant (TR) H2009 cells.

Main Results:

  • Trametinib sustained survivin suppression in RB1-positive cells by inducing p21 and dephosphorylating RB1.
  • Knockdown of p21 or RB1 partially restored survivin expression in trametinib-treated cells.
  • Trametinib showed only slight, transient survivin downregulation in RB1-negative cells, leading to rapid development of TR cells.
  • RB1-negative TR cells exhibited increased dependence on survivin for survival.

Conclusions:

  • Trametinib efficacy in KRAS-mutant lung adenocarcinomas is dependent on sustained survivin suppression, which is mediated by RB1.
  • RB1-negative status predicts trametinib resistance in KRAS-mutant lung adenocarcinomas.
  • RB1 status serves as a potential predictive biomarker for trametinib therapy in this patient population.
Keywords:
KRAS-mutant lung adenocarcinomaRB1SurvivinTrametinibp21

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