Work

Chronic lymphocytic leukemia cells from ibrutinib treated patients are sensitive to Axl receptor tyrosine kinase inhibitor therapy

Year: 2018

Type: article

Abstract: // Sutapa Sinha 1 , Justin C. Boysen 1 , Kari G. Chaffee 2 , Brian F. Kabat 2 , Susan L. Slager 2 , Sameer A. Parikh 1 , Charla R. Secreto 1 , Tim Call 1 , Tait D. Shanafelt 3 , Jose F. Leis 4 , Steven L. Warner 5 , David J. Bearss 5 , Asish K. Ghosh 6 and Neil E. Kay 1 1 Division of Hematology and Mayo Clinic, Rochester, MN, USA 2 Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA 3 Department of Medicine-Hematology, Stanford School of Medicine, Stanford, CA, USA 4 Department of Hematology and Oncology, Mayo Clinic, Scottsdale, AZ, USA 5 Tolero Pharmaceuticals, Inc., Lehi, UT, USA 6 Stephenson Cancer Center and Department of Pathology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA Correspondence to: 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 ABSTRACT 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 LD 50 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.

Source: Oncotarget

DOI: 10.18632/oncotarget.26444