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

Abstract

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.

Repression of AXL expression by AP-1/JNK blockage overcomes resistance to PI3Ka therapy

“…Indeed, small molecule inhibitors (such as BGB324, ONO-747, TP-0903, MGCD516, and BPI-9016M) or specific antibodies (CAB-AXL-ADC) that target the AXL receptor or the AXL pathway are currently under clinical evaluation in 14 clinical trials as a monotherapy or in combination with other therapies in different settings (ClinicalTrials.gov). The clinical outcomes of these studies are not yet available, but preclinical models indicate that the efficacy of a single agent targeting AXL signaling can be limited by the upregulation of other receptors, such as MERTK (41), while the potency of several combination therapies is superior to that of the monotherapies (15,40,(42)(43)(44)(45)(46)(47).…”

TAM Receptor Tyrosine Kinases in Cancer Drug Resistance

“…A recent example is from a study that showed Axl to be upregulated in CML patients that had developed resistance to BCR-Abl small-molecule inhibition, including through a T315I mutation in BCR-Abl. The selective Axl small-molecule inhibitor BGB324 inhibited the resistant CML cells independent of BCR-Abl mutational status (33). This example indicates an efficacious employment of Axl inhibition at the earliest signs of resistance development to first-line or targeted therapies.…”

AXL is a key factor for cell plasticity and promotes metastasis in pancreatic cancer

“…The efficacy of bemcentinib in combination with chemotherapy is being tested currently in pancreatic cancer patients (NCT03649321). Pharmacological inhibition of AXL has also been shown to decrease metastasis in breast cancer models (19,41) and improve the efficacy of doxorubicin, BCR-ABL inhibitor, docetaxel, paclitaxel, EGFR inhibitor and nivolumab in breast cancer, chronic myelogenous leukemia, prostate cancer, uterine serous cancer, NSCLC and glioblastoma models, respectively (11,19,(42)(43)(44)(45). (46,47).…”