Therapeutic Challenge with a CDK 4/6 Inhibitor Induces an RB-Dependent SMAC-Mediated Apoptotic Response in Non-Small Cell Lung Cancer

Clin Cancer Res. 2018 Mar 15;24(6):1402-1414. doi: 10.1158/1078-0432.CCR-17-2074. Epub 2018 Jan 8.

Abstract

Purpose: The retinoblastoma tumor suppressor (RB), a key regulator of cell-cycle progression and proliferation, is functionally suppressed in up to 50% of non-small cell lung cancer (NSCLC). RB function is exquisitely controlled by a series of proteins, including the CyclinD-CDK4/6 complex. In this study, we interrogated the capacity of a CDK4/6 inhibitor, palbociclib, to activate RB function.Experimental Design and Results: We employed multiple isogenic RB-proficient and -deficient NSCLC lines to interrogate the cytostatic and cytotoxic capacity of CDK 4/6 inhibition in vitro and in vivo We demonstrate that while short-term exposure to palbociclib induces cellular senescence, prolonged exposure results in inhibition of tumor growth. Mechanistically, CDK 4/6 inhibition induces a proapoptotic transcriptional program through suppression of IAPs FOXM1 and Survivin, while simultaneously augmenting expression of SMAC and caspase-3 in an RB-dependent manner.Conclusions: This study uncovers a novel function of RB activation to induce cellular apoptosis through therapeutic administration of a palbociclib and provides a rationale for the clinical evaluation of CDK 4/6 inhibitors in the treatment of patients with NSCLC. Clin Cancer Res; 24(6); 1402-14. ©2018 AACR.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Apoptosis Regulatory Proteins
  • Biomarkers
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / metabolism*
  • Carcinoma, Non-Small-Cell Lung / mortality
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Cyclin-Dependent Kinase 4 / antagonists & inhibitors
  • Cyclin-Dependent Kinase 6 / antagonists & inhibitors
  • Disease Models, Animal
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / mortality
  • Mice
  • Mitochondrial Proteins / metabolism*
  • Protein Kinase Inhibitors / pharmacology*
  • Reactive Oxygen Species / metabolism
  • Retinoblastoma Protein / metabolism*
  • Tumor Burden
  • Xenograft Model Antitumor Assays

Substances

  • Apoptosis Regulatory Proteins
  • Biomarkers
  • DIABLO protein, human
  • Intracellular Signaling Peptides and Proteins
  • Mitochondrial Proteins
  • Protein Kinase Inhibitors
  • Reactive Oxygen Species
  • Retinoblastoma Protein
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinase 6