AP1/Fra1 confers resistance to MAPK cascade inhibition in pancreatic cancer

Christian Schneeweis, Sandra Diersch, Zonera Hassan, Lukas Krauß, Carolin Schneider, Daniele Lucarelli, Chiara Falcomatà, Katja Steiger, Rupert Öllinger, Oliver H. Krämer, Alexander Arlt, Marian Grade, Marc Schmidt-Supprian, Elisabeth Hessmann, Matthias Wirth, Roland Rad, Maximilian Reichert, Dieter Saur, Günter Schneider

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


Targeting KRAS downstream signaling remains an important therapeutic approach in pancreatic cancer. We used primary pancreatic ductal epithelial cells and mouse models allowing the conditional expression of oncogenic KrasG12D, to investigate KRAS signaling integrators. We observed that the AP1 family member FRA1 is tightly linked to the KRAS signal and expressed in pre-malignant lesions and the basal-like subtype of pancreatic cancer. However, genetic-loss-of-function experiments revealed that FRA1 is dispensable for KrasG12D-induced pancreatic cancer development in mice. Using FRA1 gain- and loss-of-function models in an unbiased drug screen, we observed that FRA1 is a modulator of the responsiveness of pancreatic cancer to inhibitors of the RAF–MEK–ERK cascade. Mechanistically, context-dependent FRA1-associated adaptive rewiring of oncogenic ERK signaling was observed and correlated with sensitivity to inhibitors of canonical KRAS signaling. Furthermore, pharmacological-induced degradation of FRA1 synergizes with MEK inhibitors. Our studies establish FRA1 as a part of the molecular machinery controlling sensitivity to MAPK cascade inhibition allowing the development of mechanism-based therapies.

Original languageEnglish
Article number12
JournalCellular and Molecular Life Sciences
Issue number1
StatePublished - Jan 2023


  • AP1
  • ERK
  • FRA1
  • KRAS
  • MEK
  • Pancreatic cancer


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