5735 - The identification of the AXL/Gas6 signalling axis as a key player of myelodysplastic syndrome (MDS) and the potential of the oral selective AXL inhibitor bemcentinib in the treatment of MDS

Background

The progression of myelodysplastic syndrome (MDS) is driven by a rare stem cell lineage characterised as CD34⁺CD38^- (MDS-SCs). Compared to healthy cells, MDS-MSCs display de-regulation of several niche factors involved in intercellular communication, including the ligand Gas6. AXL, the high affinity Gas6 receptor, has been shown to be the only TAM receptor up-regulated in purified CD34+ MDS stem/progenitor cells. Bemcentinib (BGB324) is a selective, orally bioavailable small molecule inhibitor of AXL in phase II clinical development in AML/MDS, NSCLC, TNBC and melanoma.

Methods

The levels of Gas6 in bone marrow plasma were evaluated by ELISA in 183 untreated MDS patients. In vitro co-cultures were used to evaluate the potential of bemcentinib to modulate MDS cell proliferation and colony formation. A patient derived xenograft mouse model of MDS was used to determine the in vivo efficacy of bemcentinib.

Results

Gas6, the ligand for the AXL receptor tyrosine kinase, levels were higher in the bone marrow plasma of MDS patients (n = 183) compared to healthy individuals. Comparable Gas6 levels were observed across all MDS risk categories. The oral selective AXL inhibitor, bemcentinib, was found to reduce the frequency and impair the proliferation of CD34⁺ MDS stem progenitor cells. Bemcentinib was found to reduce the ability of MDS cells to form colonies in 2D cultures, indicating that the compound reduces both the frequency of cells with stem/progenitor potential and the expansion capability of the remaining progenitors. Treatment with bemcentinib inhibited MDS propagation in vivo as determined by a decrease in the frequency of human CD45⁺CD33⁺ MDS cells in a PDX model of MDS.

Conclusions

The Gas6/AXL axis is upregulated in MDS patients. Targeting AXL with bemcentinib was found to significantly inhibit the expansion and survival of primary patient MDS cells. This includes the stem progenitor population which has been shown to be responsible for disease propagation in vivo. These data warrant an evaluation of the targeting AXL with bemcentinib in patients with MDS.

Clinical trial identification

Legal entity responsible for the study

Georg-Speyer-Haus.

Funding

Bergenbio.

Editorial Acknowledgement

Disclosure

H. Medyouf: Research support: Janssen, Bergenbio. All other authors have declared no conflicts of interest.