eIF4A Inhibitors Suppress Cell-Cycle Feedback Response and Acquired Resistance to CDK4/6 Inhibition in Cancer

Mol Cancer Ther. 2019 Nov;18(11):2158-2170. doi: 10.1158/1535-7163.MCT-19-0162. Epub 2019 Aug 8.


CDK4/6 inhibitors are FDA-approved drugs for estrogen receptor-positive (ER+) breast cancer and are being evaluated to treat other tumor types, including KRAS-mutant non-small cell lung cancer (NSCLC). However, their clinical utility is often limited by drug resistance. Here, we sought to better understand the resistant mechanisms and help devise potential strategies to overcome this challenge. We show that treatment with CDK4/6 inhibitors in both ER+ breast cancer and KRAS-mutant NSCLC cells induces feedback upregulation of cyclin D1, CDK4, and cyclin E1, mediating drug resistance. We demonstrate that rocaglates, which preferentially target translation of key cell-cycle regulators, effectively suppress this feedback upregulation induced by CDK4/6 inhibition. Consequently, combination treatment of CDK4/6 inhibitor palbociclib with the eukaryotic initiation factor (eIF) 4A inhibitor, CR-1-31-B, is synergistic in suppressing the growth of these cancer cells in vitro and in vivo Furthermore, ER+ breast cancer and KRAS-mutant NSCLC cells that acquired resistance to palbociclib after chronic drug exposure are also highly sensitive to this combination treatment strategy. Our findings reveal a novel strategy using eIF4A inhibitors to suppress cell-cycle feedback response and to overcome resistance to CDK4/6 inhibition in cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminopyridines / pharmacology
  • Benzimidazoles / pharmacology
  • Benzofurans / chemistry
  • Benzofurans / pharmacology*
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / metabolism*
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / metabolism*
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Drug Resistance, Neoplasm* / drug effects
  • Drug Synergism
  • Eukaryotic Initiation Factor-4A / antagonists & inhibitors
  • Female
  • Humans
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism*
  • MCF-7 Cells
  • Piperazines / pharmacology
  • Protein Kinase Inhibitors / pharmacology*
  • Purines / pharmacology
  • Pyridines / pharmacology


  • Aminopyridines
  • Benzimidazoles
  • Benzofurans
  • Piperazines
  • Protein Kinase Inhibitors
  • Purines
  • Pyridines
  • rocagloic acid
  • abemaciclib
  • Eukaryotic Initiation Factor-4A
  • palbociclib
  • ribociclib