2. Academic Validation
  3. AXL Inhibition Represents a Novel Therapeutic Approach in BCR-ABL Negative Myeloproliferative Neoplasms

AXL Inhibition Represents a Novel Therapeutic Approach in BCR-ABL Negative Myeloproliferative Neoplasms

  • Hemasphere. 2021 Aug 11;5(9):e630. doi: 10.1097/HS9.0000000000000630.
Antonia Beitzen-Heineke 1 2,  Nikolaus Berenbrok 1 2 3 4,  Jonas Waizenegger 1 3,  Sarina Paesler 1 2,  Victoria Gensch 1 2 3 4,  Florian Udonta 1 2,  Maria Elena Vargas Delgado 3,  Janik Engelmann 1 2,  Friederike Hoffmann 5,  Philippe Schafhausen 1,  Gunhild von Amsberg 1,  Kristoffer Riecken 6,  Niklas Beumer 3 7 8,  Charles D Imbusch 7,  James Lorens 9 10,  Thomas Fischer 11,  Klaus Pantel 2,  Carsten Bokemeyer 1,  Isabel Ben-Batalla 1 2 3 4,  Sonja Loges 1 2 3 4
Affiliations

Affiliations

  • 1 Department for Oncology, Hematology and Bone Marrow Transplantation with the Section Pneumology, Hubertus Wald Tumorzentrum, University Comprehensive Cancer Center Hamburg, Germany.
  • 2 Department of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • 3 Division of Personalized Medical Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 4 Department of Personalized Oncology, University Hospital Mannheim, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
  • 5 Practice for Hematology and Oncology Altona, Hamburg, Germany.
  • 6 Department of Stem Cell Transplantation, Research Department Cell and Gene Therapy, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • 7 Division of Applied Bioinformatics, German Cancer Research Center (Deutsches Krebsforschungszentrum; DKFZ), Heidelberg, Germany.
  • 8 Faculty of Biosciences, Heidelberg University, Heidelberg, Germany.
  • 9 Department of Biomedicine, Centre for Cancer Biomarkers, Norwegian Centre of Excellence, University of Bergen, Norway.
  • 10 BerGenBio ASA, Bergen, Norway.
  • 11 Department of Hematology and Oncology, Medical Center, Otto-von-Guericke University, Magdeburg, Germany.
PMID: 34396051 DOI: 10.1097/HS9.0000000000000630
Abstract

Bcr-Abl negative myeloproliferative neoplasms (MPNs) consist of essential thrombocythemia, polycythemia vera, and myelofibrosis. The majority of patients harbor the JAK2-activating mutation V617F. JAK2 inhibitors were shown to reduce symptom burden and splenomegaly in MPN patients. However, treatment options are limited after failure of JAK2 inhibitors. AXL, a member of the TAM family of Receptor Tyrosine Kinases, mediates survival and therapy resistance of different myeloid cancers including acute myeloid leukemia and chronic myeloid leukemia. We studied the relevance of AXL as a target in MPN using primary patient cells and preclinical disease models. We found that AXL is abundantly activated in MPN cells and that its ligand growth arrest-specific gene 6 is upregulated in MPN patients. Pharmacologic and genetic blockade of AXL impaired viability, decreased proliferation and increased Apoptosis of MPN cells. Interestingly, ruxolitinib treatment induced increased phosphorylation of AXL indicating that activation of AXL might mediate resistance to ruxolitinib. Consistently, the AXL inhibitor bemcentinib exerted additive effects with ruxolitinib via impaired STAT3, STAT5, and Akt signaling. Both agents had activity when employed alone and exerted an additive effect on survival and splenomegaly in vivo. Moreover, bemcentinib treatment normalized red blood cell count and hemoglobin levels in vivo. Thus, our data indicate that AXL inhibition represents a novel treatment option in MPN warranting clinical investigation.

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