Ben Batalla, I. et al. (2017) Axl blockade by BGB324 inhibits BCR-ABL tyrosine kinase inhibitor-sensitive and -resistant chronic myeloid leukemia. Clinical Cancer Research, 23(9), pp. 2289-2300. (doi:10.1158/1078-0432.CCR-16-1930 This is the author's final accepted version.There may be differences between this version and the published version. You are advised to consult the publisher's version if you wish to cite from it.http://eprints.gla.ac.uk/131767/
STATEMENT OF TRANSLATIONAL RELEVANCEABL tyrosine kinase inhibitors (TKI) are employed for chronic myeloid leukemia (CML) treatment and induce durable remissions in the majority of patients. However, resistant disease and persistence of BCR-ABL1-independent leukemia stem and progenitor cells remain clinical challenges.Furthermore, ABL-TKI are associated with the risk of severe side effects in long term use. Therefore, novel therapeutic strategies are warranted to target persisting stem cells and resistant clones alone or in combination with ABL-TKI.We demonstrate here the activity of an Axl inhibitor, BGB324, against TKI-sensitive and -resistant BCR-ABL1 positive cells, including T315I-mutated and ponatinib-resistant primary cells. Inhibition of Axl with BGB324 exerted therapeutic effects in complementary T315I-mutated and ponatinib-resistant preclinical mouse models. BGB324 was well-tolerated in Phase 1 clinical trials in healthy volunteers and AML patients (BGBC001, BGBC003 ongoing). Thus our findings can be rapidly translated to the clinics and BGB324 holds promise to improve treatment of CML patients.