Abstract A053: Inhibition of the MEK5-ERK5 signaling pathway blocks pancreatic tumorigenesis

Abstract

Abstract Mutant KRAS represents one of the most common driving events in pancreatic ductal adenocarcinomas (PDAC), yet therapies targeting this pathway have proven largely ineffective. We identified ERK5 activation as critical component of KRAS-driven pancreatic tumorigenesis. ERK5 belongs to the MAP kinase family and is phosphorylated and activated by the MAPK kinase MEK5. Therefore, the aim of this study is to elucidate the function of the MEK5-ERK5 signaling axis in PDAC pathogenesis. Several novel genetically engineered mouse models with pancreas-specific deletion or activation of the MEK5-ERK5 signaling were generated to study pancreatic cancer initiation and progression. Caerulein-induced pancreatitis was performed in p48Cre/+ KrasG12D/+ (Kras) and p48Cre/+ KrasG12D/+ Erk5fl/fl (Kras;Erk5) mice to study early steps in pancreatic tumorigenesis. To investigate if ERK5 ablation impacts tumor progression a two-stage tumor model utilizing dual recombinase (Cre/Flp) mouse model was utilized. Next, the impact of ERK5 depletion or pharmacological inhibition on survival of pancreatic cancer mice was analyzed. Furthermore, human patient-derived PDAC xenograft models in immunodeficient mice were utilized to evaluate efficacy of a small molecule ERK5 inhibitor which does not exhibit off-target activity on bromodomains. Deletion of ERK5 or inhibition of its kinase activity resulted in blocked tumorigenesis in Kras mutant mice using caerulein-induced pancreatitis. Upon pancreatitis induction pancreas in Kras;Erk5 mice exhibit normal tissue architecture with significantly fewer proliferating cells compared to control mice. Intriguingly, pancreas-specific expression of constitutively active MEK5 (MEK5DD) even without oncogenic Kras mutations was sufficient in promoting development of precancerous lesions after pancreatitis induction. Next, we observed that genetic depletion or pharmacological inhibition of ERK5 significantly prolonged survival of the KPC PDAC mouse model, whereas expression of MEK5DD in KPC mice resulted in significantly accelerated tumorigenesis and reduced survival compared to control mice. Furthermore, depletion of ERK5 in already established PDAC resulted in significantly prolonged survival and reduced tumor burden indicating an important role of ERK5 in tumor maintenance. Finally, ERK5 inhibitor treatment of patient-derived PDAC xenografts in immunocompromised mice resulted in tumor growth arrest. Our studies demonstrate that the MEK5-ERK5 signaling pathway plays an important role in pancreatic cancer initiation and progression. Deletion of ERK5 or pharmacological inhibition of ERK5 kinase activity results in significantly reduced tumor burden and prolonged survival in autochthonous PDAC models and patient-derived xenografts. Conversely, activation of MEK5-ERK5 signaling is sufficient to drive pancreatic tumorigenesis indicating an essential role of the ERK5 pathway as downstream effector of oncogenic KRAS. Further studies will be performed to identify the mechanisms of ERK5 action including downstream kinase targets. Citation Format: Simone Hausmann, Asli Ece Kasapoglu, Ana Benitez Morales, Shane Lofgren, Pawel K. Mazur. Inhibition of the MEK5-ERK5 signaling pathway blocks pancreatic tumorigenesis [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A053.