Chronic lymphocytic leukemia cells from ibrutinib treated patients are sensitive to Axl receptor tyrosine kinase inhibitor therapy
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Sutapa Sinha1, Justin C. Boysen1, Kari G. Chaffee2, Brian F. Kabat2, Susan L. Slager2, Sameer A. Parikh1, Charla R. Secreto1, Tim Call1, Tait D. Shanafelt3, Jose F. Leis4, Steven L. Warner5, David J. Bearss5, Asish K. Ghosh6 and Neil E. Kay1
1Division of Hematology and Mayo Clinic, Rochester, MN, USA
2Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
3Department of Medicine-Hematology, Stanford School of Medicine, Stanford, CA, USA
4Department of Hematology and Oncology, Mayo Clinic, Scottsdale, AZ, USA
5Tolero Pharmaceuticals, Inc., Lehi, UT, USA
6Stephenson Cancer Center and Department of Pathology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
Neil E. Kay, email: [email protected]
Keywords: AXL; TP-0903; Ibrutinib; CLL; apoptosis
Received: September 07, 2018 Accepted: November 16, 2018 Published: December 14, 2018
Earlier we have shown the expression of a constitutively active receptor tyrosine kinase Axl in CLL B-cells from previously untreated CLL patients, and that Axl inhibitor TP-0903 induces robust leukemic B-cell death. To explore whether Axl is an effective target in relapsed/refractory CLL patients, we analyzed CLL B-cells obtained from CLL patients on ibrutinib therapy. Ibrutinib-exposed CLL B-cells were treated with increasing doses (0.01- 0.50μM) of a new formulation of high-affinity Axl inhibitor, TP-0903 (tartrate salt), for 24 hours and LD50 doses were determined. Sensitivity of CLL B-cells was compared with known prognostic factors and effect of TP-0903 was also evaluated on Axl signaling pathway in CLL B-cells from this cohort. We detected sustained overexpression of Axl in CLL B-cells from CLL patients on ibrutinib treatment, suggests targeting Axl could be a promising strategy to overcome drug resistance and killing of CLL B-cells in these patients. We found that CLL B-cells from sixty-nine percent of relapsed CLL patients actively on ibrutinib therapy were found to be highly sensitive to TP-0903 with induction of apoptosis at nanomolar doses (≤0.50 μM). TP-0903 treatment effectively inhibited Axl phosphorylation and reduced expression levels of anti-apoptotic proteins (Mcl-1, XIAP) in ibrutinib exposed CLL B-cells. In total, our in vitro preclinical studies showing that TP-0903 is very effective at inducing apoptosis in CLL B-cells obtained from ibrutinib-exposed patients supports further testing of this drug in relapsed/refractory CLL.
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