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

作者：Ben Batalla Isabel; Erdmann Robert; Jorgensen Heather; Mitchell Rebecca; Ernst Thomas; Von Am**erg Gunhild; Schafhausen Philippe; Velthaus Janna L; Rankin Stephen; Clark Richard E; Koschmieder Steffen; Schultze Alexander; Mitra Subir; Vandenberghe Peter; Brummendorf Tim H; Carmeliet Peter; Hochhaus Andreas; Pantel Klaus; Bokemeyer Carsten; Helgason G Vignir; Holyoake Tessa L; Loges Sonja^*

来源：Clinical Cancer Research, 2017, 23(9): 2289-2300.

DOI：10.1158/1078-0432.CCR-16-1930

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 patients with CML 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 patients with CML compared with 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 TKIsensitive 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 T315Imutated 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.

• 出版日期2017-5-1