Inhibition of activin signaling in lung adenocarcinoma increases the therapeutic index of platinum chemotherapy

Sci Transl Med. 2018 Jul 25;10(451):eaat3504. doi: 10.1126/scitranslmed.aat3504.


Resistance to platinum chemotherapy is a long-standing problem in the management of lung adenocarcinoma. Using a whole-genome synthetic lethal RNA interference screen, we identified activin signaling as a critical mediator of innate platinum resistance. The transforming growth factor-β (TGFβ) superfamily ligands activin A and growth differentiation factor 11 (GDF11) mediated resistance via their cognate receptors through TGFβ-activated kinase 1 (TAK1), rather than through the SMAD family of transcription factors. Inhibition of activin receptor signaling or blockade of activin A and GDF11 by the endogenous protein follistatin overcame this resistance. Consistent with the role of activin signaling in acute renal injury, both therapeutic interventions attenuated acute cisplatin-induced nephrotoxicity, its major dose-limiting side effect. This cancer-specific enhancement of platinum-induced cell death has the potential to dramatically improve the safety and efficacy of chemotherapy in lung cancer patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Activins / metabolism*
  • Adenocarcinoma of Lung / drug therapy*
  • Animals
  • Carboplatin / therapeutic use
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Follistatin / therapeutic use
  • Humans
  • Lung Neoplasms / drug therapy*
  • Male
  • Mice
  • Platinum / therapeutic use*
  • Signal Transduction / drug effects
  • Xenograft Model Antitumor Assays


  • Follistatin
  • Activins
  • Platinum
  • Carboplatin