TP-0903 Suppresses Aurora A–PLK1 Signaling to Inhibit Proliferation of a Myelodysplastic Syndrome-Derived Cell Line

Abstract

A low molecular compound originally developed as an anexelekto inhibitor, TP-0903, has been highlighted as a promising therapeutic agent for treating chronic lymphocytic leukemia, solid tumors, and drug-resistant AML. We investigated the in vitro effects of TP-0903 on a myelodysplastic syndrome (MDS)-derived cell line (MDS-L) and two myeloid leukemia cell lines. TP-0903 effectively inhibited cell proliferation and induced apoptosis in all three cell lines. In MDS-L cells, the PI3K/AKT and JAK/STAT3 pathways were inhibited, suggesting that this may be partly due to decreased direct interactions with hepatocyte growth factor receptor, commonly known as MET. Regarding its effect on the cell cycle, TP-0903 was found to impact the DNA damage response and cell cycle-related factors, particularly those centered around Aurora kinases. In MDS-L cells, inhibition of Aurora A phosphorylation led to decreased levels of BORA, which in turn suppressed polo-like kinase 1 activation. This suppression hindered mitosis initiation, resulting in cell cycle arrest at the G2/M phase. Additionally, chromosomal misregulation caused by Aurora A inhibition appeared to impair cell division and contribute to cell death. Gene expression profiling of MDS-L revealed changes in the ferroptosis-related genes, including HMOX1 and transferrin, along with elevated levels of reactive oxygen species and intracellular iron accumulation. These findings suggest the activation of an atypical ferroptosis pathway mediated through the TGF-β1/SMAD3 signaling pathway. Overall, these data indicate that TP-0903 may offer a novel therapeutic strategy for the treatment of refractory hematological malignancies.