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

Cell Mol Life Sci. 2022 Dec 19;80(1):12. doi: 10.1007/s00018-022-04638-y.

Christian Schneeweis ¹ ², Sandra Diersch ¹, Zonera Hassan ¹, Lukas Krauß ³, Carolin Schneider ³, Daniele Lucarelli ², Chiara Falcomatà ², Katja Steiger ⁴ ⁵, Rupert Öllinger ⁶, Oliver H Krämer ⁷, Alexander Arlt ⁸, Marian Grade ³ ⁹, Marc Schmidt-Supprian ⁵ ¹⁰, Elisabeth Hessmann ⁹ ¹¹ ¹², Matthias Wirth ¹³, Roland Rad ⁵ ⁶, Maximilian Reichert ¹ ⁵ ¹⁴, Dieter Saur ² ⁵, Günter Schneider ¹⁵ ¹⁶ ¹⁷ ¹⁸

Affiliations

1 Medical Clinic and Polyclinic II, Klinikum Rechts Der Isar, Technical University Munich, 81675, Munich, Germany.
2 Institute for Translational Cancer Research and Experimental Cancer Therapy, Technical University Munich, 81675, Munich, Germany.
3 Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, 37075, Göttingen, Germany.
4 Comparative Experimental Pathology, Institute of Pathology, School of Medicine, Technical Universität München, 81675, Munich, Germany.
5 German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), 69120, Heidelberg, Germany.
6 Institute of Molecular Oncology and Functional Genomics, TUM School of Medicine, TU München, 81675, Munich, Germany.
7 Department of Toxicology, University of Mainz Medical Center, 55131, Mainz, Germany.
8 Department for Internal Medicine and Gastroenterology, University Hospital, Klinikum Oldenburg AöR, 26133, Oldenburg, Germany.
9 CCC-N (Comprehensive Cancer Center Lower Saxony), Göttingen, Germany.
10 Institute of Experimental Hematology, School of Medicine, Technical University of Munich, 81675, Munich, Germany.
11 University Medical Center Göttingen Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, 37075, Göttingen, Germany.
12 Clinical Research Unit 5002, KFO5002, University Medical Center Göttingen, 37075, Göttingen, Germany.
13 Department of Hematology, Oncology and Tumor Immunology, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, 12203, Berlin, Germany.
14 Translational Pancreatic Research Cancer Center, Medical Clinic and Polyclinic II, Klinikum Rechts Der Isar, Technical University Munich, 81675, Munich, Germany.
15 Medical Clinic and Polyclinic II, Klinikum Rechts Der Isar, Technical University Munich, 81675, Munich, Germany. [email protected].
16 Institute for Translational Cancer Research and Experimental Cancer Therapy, Technical University Munich, 81675, Munich, Germany. [email protected].
17 Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, 37075, Göttingen, Germany. [email protected].
18 CCC-N (Comprehensive Cancer Center Lower Saxony), Göttingen, Germany. [email protected].

PMID: 36534167 DOI: 10.1007/s00018-022-04638-y

Abstract

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.

Keywords

AP1; ERK; FRA1; KRAS; MEK; Pancreatic cancer.

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