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Axl Blockade by BGB324 Inhibits BCR-ABL Tyrosine Kinase Inhibitor-Sensitive and -Resistant Chronic Myeloid Leukemia

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Axl Blockade by BGB324 Inhibits BCR-ABL Tyrosine Kinase Inhibitor-Sensitive and -Resistant Chronic Myeloid Leukemia. / Ben Batalla, Isabel; Erdmann, Robert; Jørgensen, Heather; Mitchell, Rebecca; Ernst, Thomas; von Amsberg, Gunhild; Schafhausen, Philippe; Velthaus, Janna L; Rankin, Stephen; Clark, Richard E; Koschmieder, Steffen; Schultze, Alexander; Mitra, Subir; Vandenberghe, Peter; Brümmendorf, Tim H; Carmeliet, Peter; Hochhaus, Andreas; Pantel, Klaus; Bokemeyer, Carsten; Helgason, G Vignir; Holyoake, Tessa L; Loges, Sonja.

In: CLIN CANCER RES, Vol. 23, No. 9, 01.05.2017, p. 2289-2300.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Ben Batalla, I, Erdmann, R, Jørgensen, H, Mitchell, R, Ernst, T, von Amsberg, G, Schafhausen, P, Velthaus, JL, Rankin, S, Clark, RE, Koschmieder, S, Schultze, A, Mitra, S, Vandenberghe, P, Brümmendorf, TH, Carmeliet, P, Hochhaus, A, Pantel, K, Bokemeyer, C, Helgason, GV, Holyoake, TL & Loges, S 2017, 'Axl Blockade by BGB324 Inhibits BCR-ABL Tyrosine Kinase Inhibitor-Sensitive and -Resistant Chronic Myeloid Leukemia', CLIN CANCER RES, vol. 23, no. 9, pp. 2289-2300. https://doi.org/10.1158/1078-0432.CCR-16-1930

APA

Ben Batalla, I., Erdmann, R., Jørgensen, H., Mitchell, R., Ernst, T., von Amsberg, G., Schafhausen, P., Velthaus, J. L., Rankin, S., Clark, R. E., Koschmieder, S., Schultze, A., Mitra, S., Vandenberghe, P., Brümmendorf, T. H., Carmeliet, P., Hochhaus, A., Pantel, K., Bokemeyer, C., ... Loges, S. (2017). Axl Blockade by BGB324 Inhibits BCR-ABL Tyrosine Kinase Inhibitor-Sensitive and -Resistant Chronic Myeloid Leukemia. CLIN CANCER RES, 23(9), 2289-2300. https://doi.org/10.1158/1078-0432.CCR-16-1930

Vancouver

Ben Batalla I, Erdmann R, Jørgensen H, Mitchell R, Ernst T, von Amsberg G et al. Axl Blockade by BGB324 Inhibits BCR-ABL Tyrosine Kinase Inhibitor-Sensitive and -Resistant Chronic Myeloid Leukemia. CLIN CANCER RES. 2017 May 1;23(9):2289-2300. https://doi.org/10.1158/1078-0432.CCR-16-1930

Bibtex

@article{efb7166691184297bbb6307ce41f0ea5,
title = "Axl Blockade by BGB324 Inhibits BCR-ABL Tyrosine Kinase Inhibitor-Sensitive and -Resistant Chronic Myeloid Leukemia",
abstract = "PURPOSE: BCR-ABL kinase inhibitors are employed successfully for chronic myeloid leukemia (CML) treatment. However, resistant disease and persistence of BCR-ABL1-independent leukemia stem and progenitor cells (LSPC) remain clinical challenges. The receptor tyrosine kinase Axl can mediate survival and therapy resistance of different cancer cells. We investigated the therapeutic potential of Axl inhibition in CML.EXPERIMENTAL DESIGN: We used primary cells from CML patients and TKI-sensitive and -resistant BCR-ABL1+ CML cell lines and a novel Ponatinib-resistant cell line KCL-22 PonR. We analyzed the effects of genetic and pharmacologic Axl blockade by the small molecule Axl inhibitor BGB324 in vitro and in vivo. In BCR-ABL1 unmutated cells we also investigated BGB324 in combination with imatinib.RESULTS: We demonstrate overexpression of Axl receptor tyrosine kinase in primary cells of CML patients compared to healthy individuals, and a further increase of Axl expression in BCR-ABL TKI-resistant patients. We show that Axl blockage decreased growth of BCR-ABL TKI-sensitive CML cells including CD34+ cells and exerts additive effects with imatinib via inhibition of Stat5 activation. BGB324 also inhibits BCR-ABL TKI-resistant cells, including T315I-mutated and ponatinib-resistant primary cells. BGB324 exerted therapeutic effects in BCR-ABL1 T315I-mutated and ponatinib-resistant preclinical mouse models. Notably, BGB324 does not inhibit BCR-ABL1 and consequently inhibits CML independent of BCR-ABL1 mutational status.CONCLUSIONS: Our data show that Axl inhibition has therapeutic potential in BCR-ABL TKI-sensitive as well as resistant CML and support the need for clinical trials.",
author = "{Ben Batalla}, Isabel and Robert Erdmann and Heather J{\o}rgensen and Rebecca Mitchell and Thomas Ernst and {von Amsberg}, Gunhild and Philippe Schafhausen and Velthaus, {Janna L} and Stephen Rankin and Clark, {Richard E} and Steffen Koschmieder and Alexander Schultze and Subir Mitra and Peter Vandenberghe and Br{\"u}mmendorf, {Tim H} and Peter Carmeliet and Andreas Hochhaus and Klaus Pantel and Carsten Bokemeyer and Helgason, {G Vignir} and Holyoake, {Tessa L} and Sonja Loges",
note = "Copyright {\textcopyright}2016, American Association for Cancer Research.",
year = "2017",
month = may,
day = "1",
doi = "10.1158/1078-0432.CCR-16-1930",
language = "English",
volume = "23",
pages = "2289--2300",
journal = "CLIN CANCER RES",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "9",

}

RIS

TY - JOUR

T1 - Axl Blockade by BGB324 Inhibits BCR-ABL Tyrosine Kinase Inhibitor-Sensitive and -Resistant Chronic Myeloid Leukemia

AU - Ben Batalla, Isabel

AU - Erdmann, Robert

AU - Jørgensen, Heather

AU - Mitchell, Rebecca

AU - Ernst, Thomas

AU - von Amsberg, Gunhild

AU - Schafhausen, Philippe

AU - Velthaus, Janna L

AU - Rankin, Stephen

AU - Clark, Richard E

AU - Koschmieder, Steffen

AU - Schultze, Alexander

AU - Mitra, Subir

AU - Vandenberghe, Peter

AU - Brümmendorf, Tim H

AU - Carmeliet, Peter

AU - Hochhaus, Andreas

AU - Pantel, Klaus

AU - Bokemeyer, Carsten

AU - Helgason, G Vignir

AU - Holyoake, Tessa L

AU - Loges, Sonja

N1 - Copyright ©2016, American Association for Cancer Research.

PY - 2017/5/1

Y1 - 2017/5/1

N2 - PURPOSE: BCR-ABL kinase inhibitors are employed successfully for chronic myeloid leukemia (CML) treatment. However, resistant disease and persistence of BCR-ABL1-independent leukemia stem and progenitor cells (LSPC) remain clinical challenges. The receptor tyrosine kinase Axl can mediate survival and therapy resistance of different cancer cells. We investigated the therapeutic potential of Axl inhibition in CML.EXPERIMENTAL DESIGN: We used primary cells from CML patients and TKI-sensitive and -resistant BCR-ABL1+ CML cell lines and a novel Ponatinib-resistant cell line KCL-22 PonR. We analyzed the effects of genetic and pharmacologic Axl blockade by the small molecule Axl inhibitor BGB324 in vitro and in vivo. In BCR-ABL1 unmutated cells we also investigated BGB324 in combination with imatinib.RESULTS: We demonstrate overexpression of Axl receptor tyrosine kinase in primary cells of CML patients compared to healthy individuals, and a further increase of Axl expression in BCR-ABL TKI-resistant patients. We show that Axl blockage decreased growth of BCR-ABL TKI-sensitive CML cells including CD34+ cells and exerts additive effects with imatinib via inhibition of Stat5 activation. BGB324 also inhibits BCR-ABL TKI-resistant cells, including T315I-mutated and ponatinib-resistant primary cells. BGB324 exerted therapeutic effects in BCR-ABL1 T315I-mutated and ponatinib-resistant preclinical mouse models. Notably, BGB324 does not inhibit BCR-ABL1 and consequently inhibits CML independent of BCR-ABL1 mutational status.CONCLUSIONS: Our data show that Axl inhibition has therapeutic potential in BCR-ABL TKI-sensitive as well as resistant CML and support the need for clinical trials.

AB - PURPOSE: BCR-ABL kinase inhibitors are employed successfully for chronic myeloid leukemia (CML) treatment. However, resistant disease and persistence of BCR-ABL1-independent leukemia stem and progenitor cells (LSPC) remain clinical challenges. The receptor tyrosine kinase Axl can mediate survival and therapy resistance of different cancer cells. We investigated the therapeutic potential of Axl inhibition in CML.EXPERIMENTAL DESIGN: We used primary cells from CML patients and TKI-sensitive and -resistant BCR-ABL1+ CML cell lines and a novel Ponatinib-resistant cell line KCL-22 PonR. We analyzed the effects of genetic and pharmacologic Axl blockade by the small molecule Axl inhibitor BGB324 in vitro and in vivo. In BCR-ABL1 unmutated cells we also investigated BGB324 in combination with imatinib.RESULTS: We demonstrate overexpression of Axl receptor tyrosine kinase in primary cells of CML patients compared to healthy individuals, and a further increase of Axl expression in BCR-ABL TKI-resistant patients. We show that Axl blockage decreased growth of BCR-ABL TKI-sensitive CML cells including CD34+ cells and exerts additive effects with imatinib via inhibition of Stat5 activation. BGB324 also inhibits BCR-ABL TKI-resistant cells, including T315I-mutated and ponatinib-resistant primary cells. BGB324 exerted therapeutic effects in BCR-ABL1 T315I-mutated and ponatinib-resistant preclinical mouse models. Notably, BGB324 does not inhibit BCR-ABL1 and consequently inhibits CML independent of BCR-ABL1 mutational status.CONCLUSIONS: Our data show that Axl inhibition has therapeutic potential in BCR-ABL TKI-sensitive as well as resistant CML and support the need for clinical trials.

U2 - 10.1158/1078-0432.CCR-16-1930

DO - 10.1158/1078-0432.CCR-16-1930

M3 - SCORING: Journal article

C2 - 27856601

VL - 23

SP - 2289

EP - 2300

JO - CLIN CANCER RES

JF - CLIN CANCER RES

SN - 1078-0432

IS - 9

ER -