Preclinical combination of TP-0903, an AXL inhibitor and B-PAC-1, a procaspase-activating compound with ibrutinib in chronic lymphocytic leukemia

Purpose: B-cell chronic lymphocytic leukemia (CLL) remains an incurable disease despite aggressive treatment strategies. Our previous research identified the Axl receptor tyrosine kinase (RTK) as a critical player in the survival of CLL B cells. In this study, we investigate the potential of using a high-affinity Axl inhibitor, either alone or in combination with Bruton’s tyrosine kinase (BTK) inhibitors, as a therapeutic approach for CLL patients in future clinical trials.

Experimental Design: We assessed the expression and activation of other members of the TAM (Tyro3, Axl, and Mer) RTK family in CLL B cells. CLL B cells were treated with TP-0903, a high-affinity, orally bioavailable Axl inhibitor, both with and without the presence of CLL bone marrow stromal cells (BMSCs). The effects of TP-0903 on Axl signaling were evaluated in these cells. Finally, we examined the potential synergistic or additive effects of combining TP-0903 with BTK inhibitors.

Results: CLL B cells overexpress Tyro3 but not Mer, and Tyro3 remains constitutively phosphorylated, forming a complex with Axl in these cells. Treatment with TP-0903 induced significant apoptosis in CLL B cells, with LD50 values in the nanomolar range. Notably, CLL BMSCs were unable to protect the leukemic B cells from TP-0903-induced apoptosis. Axl inhibition led to a marked reduction in the anti-apoptotic proteins Mcl-1, Bcl-2, and XIAP, along with an upregulation of the pro-apoptotic protein BIM in CLL B cells. Additionally, combining TP-0903 with BTK inhibitors further enhanced CLL B-cell apoptosis.

Conclusions: The administration of TP-0903, either as a monotherapy or in combination with BTK inhibitors, shows promising potential as an effective treatment strategy Dubermatinib for patients with CLL.