PDGFR-β As a New Therapeutic Target in T-Cell Acute Lymphoblastic Leukemia

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy that accounts for 10-15% of pediatric and 25% of adult ALL cases. General prognosis of T-ALL has been improving over time. However, the outcome of T-ALL patients with primary resistant or relapsed leukemia remains dismal.

PDGFR-β is a transmembrane glycoprotein dimer molecule that functions as a receptor tyrosine kinase. Ligand binding (PDGF-B/PDGF-D) results in receptor dimerization and subsequent activation via autophosphorylation, causing the downstream activation of various signaling pathways such as PI3K/AKT, MAPK/ERK, JAK/STAT and Notch.

During normal T cell development, PDGFR-β is expressed in the double negative stage in CD34⁺ T-cells and drops dramatically once CD34 is lost. The expression of both ligands, PDGF-B and PDGF-D, seems to be restricted to γδ CD3⁺ CD1^- T-cells. We looked in vivo to the effect of PDGFR-β overexpression on normal T cell development making use of CD2-iCre driven overexpression of PDGFR- β in a C57Bl6 background. Overexpression of PDGFR-β in the R26-locus did not affect normal T-cell development.

In T-ALL patients, high PDGFR-β expression can be observed in the HOXA and TLX3 subgroups. These subgroups have significantly higher PDGFR-β expression compared to normal developing T-cells.

As constitutively active PDGFR-β is observed in a variety of malignancies, multi-target kinase inhibitors are already used in the clinic. However, they are not specific and often result in adverse side-effects.

CP-673451 is a novel, potent and selective PDGFR inhibitor. Mechanistically, CP-673451 inhibits autophosphorylation of dimeric PDGFR-β and in this way prevents phosphorylation of downstream PI3K/AKT, GSK-3α and GSK-3β. Previous studies showed growth inhibition of multiple tumor xenografts (lung and colon carcinomas, glioblastoma) mainly due to a direct antitumor effect.

Previously, we demonstrated the efficacy of CP-673451 on a T-ALL (IC₅₀=544 nM) and a B-ALL cell line (IC₅₀=500nM) with high PDGFR-β expression, as well as on a T-ALL PDX model with high levels of PDGFR-β (IC₅₀=1,6 nM). Both cell lines and PDX models showed phosphorylation of the PDGFR-β receptor. After PDGFR-β inhibition, a decrease of PDGFR-β could be observed as a negative feedback loop. Also, phosphorylation of the receptor itself decreased which resulted downstream in a downregulated phosphorylation levels of GSK3β (Ser9), STAT3 (Tyr705) and STAT5 (Tyr694). Combination experiments with glucocorticoids (Fig. A) and chemotherapy (Fig. B), currently used as conventional therapy in T-ALL, showed a synergistic effect when combined with PDGFR-β inhibition.

In conclusion, we have shown that specific PDGFR-β inhibitors can be used as a novel and targeted therapy in PDGFR-β^high T-ALL patients and that they can be of added value to the current chemotherapy treatment for T-ALL patients.

No relevant conflicts of interest to declare.