Purpose: The Hedgehog signaling pathway is a key regulator of cell growth and differentiation during development. While the Hedgehog pathway is inactive in most normal adult tissues, Hedgehog pathway reactivation has been implicated in the pathogenesis of several neoplasms including BCR-ABL1-positive leukemia. The clear link between the Hedgehog pathway and BCR-ABL1 positive leukemia led to an effort to identify small molecules to block the pathway. Experimental Design: We investigated the combined effects of vismodegib and ponatinib, a pan-ABL1 kinase inhibitor, in NOD/SCID re-populating T315I BCR-ABL1-positive cells in vitro and in vivo. Results: We observed that combination with vismodegib and ponatinib helps to eliminate therapy-resistant NOD/SCID re-populating T315I BCR-ABL1-positive cells. The percentage of CD19 positive leukemia cells in peripheral blood was significantly lower in vismodegib + ponatinib -treated mice than that of the vehicle or ponatinib alone (p< 0.001). Spleen weights were also lowesr in vismodegib + ponatinib-treated mice compared to ponatinib alone (p < 0.05). Overall tumor burden, as assessed by BCR-ABL mRNA from bone marrow cells, was significantly lower in vismodegib + ponatinib -treated mice compared to ponatinib alone (p < 0.005). We also found that vismodegib significantly reduced BCR-ABL1-positive leukemia cell self-renewal in vitro as well as during serial transplantation in vivo. Conclusions: The combination with a Smo inhibitor and ABL1 tyrosine kinase inhibitors (TKIs) may help eliminate therapy-resistant T315I BCR-ABL1 positive leukemia cells. Our preclinical results indicate that vismodegib has potential as an important option for controlling minimal residual cells in BCR-ABL1 positive leukemia.
- Received June 5, 2012.
- Revision received November 17, 2012.
- Accepted December 17, 2012.
- Copyright © 2013, American Association for Cancer Research.