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

Christian Schneeweis1,2, Sandra Diersch1, Zonera Hassan1

  • 1Medical Clinic and Polyclinic II, Klinikum Rechts Der Isar, Technical University Munich, 81675, Munich, Germany.

Cellular and Molecular Life Sciences : CMLS
|December 19, 2022
PubMed

Insights

FRA1 is linked to KRAS signaling in pancreatic cancer but dispensable for tumor development. It modulates responses to RAF-MEK-ERK inhibitors, suggesting FRA1 targeting could enhance cancer therapies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Signaling

Background:

  • Targeting KRAS downstream signaling is crucial for pancreatic cancer therapy.
  • FRA1, an AP1 family member, is associated with KRAS signaling and present in early pancreatic lesions and basal-like pancreatic cancer.
  • The role of FRA1 in Kras-driven pancreatic cancer progression and therapeutic response requires elucidation.

Purpose of the Study:

  • To investigate the role of FRA1 in Kras-driven pancreatic cancer.
  • To determine FRA1's impact on sensitivity to RAF-MEK-ERK pathway inhibitors.
  • To explore FRA1 as a therapeutic target in pancreatic cancer.

Main Methods:

  • Utilized primary pancreatic ductal epithelial cells and genetically engineered mouse models with conditional oncogenic Kras expression.
  • Conducted unbiased drug screens using FRA1 gain- and loss-of-function models.
  • Performed mechanistic studies to understand FRA1's role in ERK signaling and drug sensitivity.

Main Results:

  • FRA1 is linked to KRAS signaling and expressed in pre-malignant pancreatic lesions and basal-like pancreatic cancer.
  • FRA1 is not essential for KrasG12D-induced pancreatic cancer development in mice.
  • FRA1 modulates pancreatic cancer cell sensitivity to RAF-MEK-ERK inhibitors.
  • FRA1-associated adaptive rewiring of ERK signaling correlates with sensitivity to KRAS pathway inhibitors.
  • Pharmacological degradation of FRA1 synergizes with MEK inhibitors.

Conclusions:

  • FRA1 is a key modulator of sensitivity to MAPK cascade inhibition in pancreatic cancer.
  • Targeting FRA1, potentially through degradation, can synergize with MEK inhibitors.
  • These findings support the development of mechanism-based therapies targeting FRA1 for pancreatic cancer.
Keywords:
AP1ERKFRA1KRASMEKPancreatic cancer

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