Journal Article

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

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

2023

Overview

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 Kras G12D , 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 Kras G12D -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.

• Publisher: Springer Science and Business Media LLC,Springer International Publishing,Springer Nature B.V
• Subject: Animal models / Animals / Biochemistry / Biomedical and Life Sciences / Biomedicine / Cancer / carcinogenesis / Carcinoma, Pancreatic Ductal / Carcinoma, Pancreatic Ductal - pathology / Cell Biology / Cell culture / Cell Line, Tumor / Drug screening / drugs / Epithelial cells / Epithelium / Fra1 protein / Inhibitors / Life Sciences / loss-of-function mutation / MAP kinase / MEK inhibitors / Mice / Mitogen-Activated Protein Kinase Kinases / Mitogen-Activated Protein Kinase Kinases - metabolism / Molecular machines / Mutation / Original / Original Article / Original Article ; Pancreatic cancer ; KRAS ; MEK ; ERK ; AP1 ; FRA1 ; Medical and Health Sciences / Pancreatic cancer / Pancreatic Neoplasms / Pancreatic Neoplasms - pathology / Proto-Oncogene Proteins c-fos / Proto-Oncogene Proteins c-fos - metabolism / Proto-Oncogene Proteins p21(ras) / Raf protein / Sensitivity / Signaling / therapeutics / Transcription factors