Clinical cancer research : an official journal of the American Association for Cancer Research · 2013
Combination of ponatinib with Hedgehog antagonist vismodegib for therapy-resistant BCR-ABL1-positive leukemia.
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Katagiri Seiichiro, Tauchi Tetsuzo, Okabe Seiichi, Minami Yosuke, Kimura Shinya, Maekawa Taira, Naoe Tomoki, Ohyashiki Kazuma
Аннотация
PURPOSE: The Hedgehog signaling pathway is a key regulator of cell growth and differentiation during development. Whereas 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 nonobese diabetic/severe-combined immunodeficiency (NOD/SCID) repopulating 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 repopulating 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 lower in vismodegib + ponatinib-treated mice than in 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 than in 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 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.
EXPERIMENTAL DESIGN: We investigated the combined effects of vismodegib and ponatinib, a pan-ABL1 kinase inhibitor, in nonobese diabetic/severe-combined immunodeficiency (NOD/SCID) repopulating 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 repopulating 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 lower in vismodegib + ponatinib-treated mice than in 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 than in 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 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.