As very few novel AML drugs have been approved in the past 20 years, there is an urgent need to identify novel targets and therapeutic strategies to treat underserved AML patients. Axl is a member of the TAM family of receptor tyrosine kinases (TAMRs) together with Sky or Tyro3 and Mer. Members of the TAMR family are abundantly expressed in physiological and malignant hematopoiesis. Axl, the receptor for Growth Arrest-specific protein 6 (Gas6) has been found to play a role in AML pathobiology and therapy resistance. Furthermore, Axl expression confers worse prognosis to AML patients. Gas6 exerts pleiotropic effects in pathobiology and promotes proliferation and survival of different cancer cell lines in vitro.
The study showed higher expression of Axl in AML bone marrow BM and that BerGenBio’s Axl inhibitor BGB324 dose-dependently inhibited proliferation of primary AML cells. Sensitivity towards BGB324 correlated with Axl expression on leukemia cells. Combination therapy with BGB324 and cytarabine exerted an additive therapeutic effect and BGB324 was found to chemosensitize cytarabine-resistant AML cells. Analyses revealed that Gas6 expression was low in AML cells, similar to healthy hematopoietic cells, while it was abundantly expressed in AML BM stromal cells with fibroblastic/mesenchymal morphology (BMDSCs). Gas6 expression was considerably lower in control BMDSCs, suggesting a possible paracrine interaction between AML cells and BMDSCs leading to Gas6 upregulation in the stroma compartment. The interaction between stroma-derived Gas6 and Axl+ leukemia cells forms a chemoprotective niche for leukemia cells. In line with these findings Axl blockade chemosensitizes Mv4-11 cells for treatment with doxorubicine in vivo.
Richard Godfrey, CEO of BerGenBio, added ‘Dr. Loges’s work has built up a compelling picture of the key role that Axl and its signaling pathway play in AML pathobiology in forming a chemoprotective niche, presenting a promising therapeutic target in AML. The results demonstrate that Axl inhibition by BGB324 has the potential to treat chemosensitive and chemoresistant AML.’
BerGenBio is a spin-off company from University of Bergen, and was established by two scientists from the Department of Biomedicine, Professor Jim Lorens and Dr. David Micklem, in cooperation with BTO in 2007.