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Combination of Ponatinib with Hedgehog Antagonist Vismodegib for Therapy-Resistant BCR-ABL1–Positive Leukemia

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Combination of Ponatinib with Hedgehog Antagonist Vismodegib for Therapy-Resistant BCR-ABL1–Positive Leukemia Published OnlineFirst January 14, 2013; DOI: 10.1158/1078-0432.CCR-12-1777 Clinical Cancer Cancer Therapy: Preclinical Research See related commentary by Dao and Tyner, p. 1309 Combination of Ponatinib with Hedgehog Antagonist Vismodegib for Therapy-Resistant BCR-ABL1–Positive Leukemia Seiichiro Katagiri1, Tetsuzo Tauchi1, Seiichi Okabe1, Yosuke Minami2, Shinya Kimura3, Taira Maekawa4, Tomoki Naoe2, and Kazuma Ohyashiki1 Abstract 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 þ ponatinib–treated mice than that of the vehicle or ponatinib alone (P < 0.001). Spleen weights were also lower in vismodegib þ 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 þ 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. Clin Cancer Res; 19(6); 1422–32. Ó2012 AACR. Introduction common set of critical stemness genes that regulate self- An emerging concept in cancer biology is that a rare renewal (3). Hematopoietic stem cells and leukemic stem population of cancer stem cells exists in the heterogeneous cells share common features, including self-renewal, the cell mass that constitutes a tumor (1). This concept also capacity to differentiate, resistance to apoptosis, and limit- applies to BCR-ABL1–positive leukemia (2). Normal and less proliferative potential (3). Despite these similarities, leukemic hematopoietic stem cell functions are defined by a several stemness factors, such as Hedgehog, Wnt, Notch, and BMI-1, show differential activation in normal versus leukemia stem cells (4). Authors' Affiliations: 1First Department of Internal Medicine, Tokyo Hedgehog signaling is increased in BCR-ABL1–positive 2 Medical University, Shinjuku-ku, Tokyo; Department of Hematology and stem and progenitor cells becoming more active with Oncology, Nagoya University Graduate School of Medicine, Nagoya; 3Division of Hematology, Respiratory Medicine and Oncology, Department disease progression (5–7). The Hedgehog signaling path- of Internal Medicine, Faculty of Medicine, Saga University, Saga; and way consists of 3 closely related ligands, Sonic Hedgehog 4Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Kyoto, Japan (Shh), Indian Hedgehog (Ihh), and Desert Hedgehog (Dhh), that can each bind to the transmembrane protein Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). Patched (PTCH; refs. 8–10). Upon ligand binding, PTCH inhibition of the positive effector Smoothened (Smo) is Corresponding Author: Tetsuzo Tauchi, Division of Hematology, Depart- ment of Medicine, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinju- released and leads to production of activating forms of kuku, Tokyo 160-0023, Japan. Phone: 81-3-3342-6111; Fax: 81-3-5381- glioma-associated oncoproteins 1–3 (Gli1–3; refs. 9–12). 6651; E-mail: [email protected] Gli1 is a positive effector of signaling, Gli3 is predomi- doi: 10.1158/1078-0432.CCR-12-1777 nantly a transcriptional inhibitor, and Gli2 can function Ó2012 American Association for Cancer Research. in both roles (9–12). Smo signals to a cytoplasmic 1422 Clin Cancer Res; 19(6) March 15, 2013 Downloaded from clincancerres.aacrjournals.org on October 1, 2021. © 2013 American Association for Cancer Research. Published OnlineFirst January 14, 2013; DOI: 10.1158/1078-0432.CCR-12-1777 Targeting the Hedgehog Pathway in BCR-ABL1–Positive Leukemia Materials and Methods Translational Relevance Antibodies and reagents Despite the great success with combination of high- Anti-Gli1 Ab, anti-ABL Ab (11-23), anti-CD19 Ab, anti- dose ABL tyrosine kinases and intensive chemotherapy Bcl2 Ab, anti-Cyclin D2 Ab, and anti-c-Myc Ab were pur- in BCR-ABL1–positive acute lymphoblastic leukemia, chased from Santa Cruz Biotechnology, Inc. Human Gli1 there are still drawbacks that need to be addressed. siRNA and Smo siRNA were also purchased from Santa Cruz Above all, 40% of patients, even with hematopoietic Biotechnology, Inc. Vismodegib, ponatinib, sorafenib, and stem cell transplantation, have relapse of the disease. BEZ235 were obtained from Selleck. Therefore, it is necessary to define targets in BCR- ABL1–positive leukemia stem cells that may be candi- Cells and cell culture dates for new treatment options. In the present study, BaF3 cells expressing wild-type BCR-ABL and mutant we investigated the combined effects of vismodegib forms of BCR-ABL (M244V, G250E, Q252H, Y253F, and ponatinib in mutant forms of BCR-ABL1–expres- T315A, T315I, F317L, F317V, M351T, H396P) were sing leukemia cells. We observed that combination described previously (25, 26). SK-9 was described previ- with a Smo inhibitor and pan-ABL1 tyrosine kinase ously (27). Briefly, SK-9 cell line was established from a inhibitors (TKI) helps to eliminate therapy-resistant BCR-ABL1–positive acute lymphoblastic leukemia (ALL) T315I BCR-ABL1–positive leukemia cells. Thus, patient with T315I mutation (27). K562 cells were obtained exploring a vast array of possible therapeutic combi- from the American Type Culture Collection. OM;922 cells nations will be useful to simultaneously target these were described previously (28). TF-1 BCCR-ABL was pathways. Our preclinical results indicate that vismo- described previously (29) degib has potential as an important option for con- trolling resistance in BCR-ABL1–positive leukemia. NOD/SCID repopulating BCR-ABL1–positive cells The combined results of cell-based and in vivo studies We serially transplanted human leukemia cells from suggest that vismodegib exhibits sufficient activity patients with chronic myeloid leukemia blast crisis against mutant forms of BCR-ABL1 to warrant consid- (T315I BCR-ABL1: UPN1) or Ph-positive ALL (WT- À À eration for combined use with ABL TKIs. BCR-ABL1: UPN5) into NOD/SCID/IL-2gc / mice. The þ À þ þ cell fractions with CD34 CD38 CD19 and CD34 þ þ CD38 CD19 could self-renew and transfer the leukemia in nonobese diabetic/severe-combined immunodeficien- complex that releases Gli1, which translocates to the cy (NOD/SCID) mice (30). UPN1 cells and UPN5 cells nucleus where it activates the Hedgehog target genes were used as the NOD/SCID repopulating cells. (9, 10, 13). Leukemia cells are believed to rely on auto- crine and paracrine Hedgehog signaling. The clear link Apoptosis assay between the Hedgehog pathway and BCR-ABL1–positive The incidence of apoptosis was determined by flow leukemias led to an effort to identify small molecules to cytometric analysis with the fluorescein isothiocyanate block the pathway. (FITC)-conjugated APO2.7 monoclonal antibody (clone Vismodegib is a selective hedgehog pathway inhibitor 2.7), which was raised against the 38-kDa mitochondrial with greater potency and more favorable pharmaceutical membrane protein (7A6 antigen) and is expressed by cells properties than cyclopamine (14–19). Vismodegib has undergoing apoptosis (28). antitumor activity in a mouse model of medulloblastoma and in xenograft models of primary human tumor cells, siRNA experiments including colorectal cancer and pancreatic carcinoma, in siRNA experiments were carried out as described previ- which its effects correlate with blockade of the Hedgehog ously (26). pathway (20–23). In the present study, we investigated the combined effects Transfection of vismodegib and ponatinib, a pan-ABL1 kinase inhibitor Activated Akt1 cDNA in pUSEamp was purchased from (24), in mutant forms of BCR-ABL1–expressing BaF3 cells Millipore. Transfection experiments were carried out as and the T315I-expressing human leukemia cells. We described previously (31). observed that combination with a Smo inhibitor and ABL1 tyrosine kinase inhibitors (TKI) helps to eliminate therapy- Immunoblotting resistant T315I BCR-ABL1–positive leukemia cells. Our Immunoblotting was conducted as described previously preclinical results indicate that vismodegib has potential (31). Nuclear extracts were prepared as described previously as an important option for controlling minimal residual (32) cells in BCR-ABL1–positive leukemia. The combined
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