ACY-1215 and bortezomib cooperatively disrupt NOTCH3 signaling and induce anti-tumor effects in T-ALL models.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive lymphoproliferative disorder that accounts for approximately 10–15% of pediatric and 25% of adult cases of acute lymphoblastic leukemia (ALL) and is associated with a poor prognosis, particularly in adults. In T-ALL, research has predominantly focused on the oncogenic role of NOTCH1. However, a growing body of evidence indicates that NOTCH3 also contributes to leukemogenesis and plays a non-redundant role in the disease. Furthermore, overexpression of NOTCH3 was reported in several solid tumors, including breast, ovarian, and non-small cell lung cancers (NSCLC), with functional studies supporting its oncogenic role in these malignancies. A few years ago, we identified HDAC6 as a key regulator of NOTCH3 degradation in cancer cells and demonstrated that tubacin, a compound which inhibits HDAC6, impairs NOTCH3 stability and signaling in T-ALL cells. In the present study, we demonstrate that ACY-1215, an HDAC6 inhibitor currently in clinical trials, effectively reduces NOTCH3 levels in T-ALL cells and exhibits synergistic effects with the proteasome inhibitor bortezomib. Importantly, in vivo experiments using TALL-1 cells—a NOTCH3-addicted T-ALL model—showed that the combination of ACY-1215 and bortezomib significantly suppresses leukemia progression. Given that both drugs have acceptable safety profiles in patients, we propose that this combination warrants further clinical evaluation in tumors characterized by NOTCH3 overexpression.