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

Sutapa Sinha, Justin C. Boysen, Kari G. Chaffee, Brian F. Kabat, Susan L Slager, Sameer A Parikh, Charla R. Secreto, Tim Call, Tait D. Shanafelt, Jose F. Leis, Steven L. Warner, David J. Bearss, Asish K. Ghosh, Neil Elliot Kay

Research output: Contribution to journalArticle

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 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.

Original languageEnglish (US)
Pages (from-to)37173-37184
Number of pages12
JournalOncotarget
Volume9
Issue number98
StatePublished - Dec 1 2018

Fingerprint

B-Cell Chronic Lymphocytic Leukemia
B-Lymphocytes
Therapeutics
PCI 32765
axl receptor tyrosine kinase
Apoptosis
Apoptosis Regulatory Proteins
Lethal Dose 50
Drug Resistance
TP-0903
Cell Death
Salts
Phosphorylation

Keywords

  • Apoptosis
  • AXL
  • CLL
  • Ibrutinib
  • TP-0903

ASJC Scopus subject areas

  • Oncology

Cite this

Chronic lymphocytic leukemia cells from ibrutinib treated patients are sensitive to Axl receptor tyrosine kinase inhibitor therapy. / Sinha, Sutapa; Boysen, Justin C.; Chaffee, Kari G.; Kabat, Brian F.; Slager, Susan L; Parikh, Sameer A; Secreto, Charla R.; Call, Tim; Shanafelt, Tait D.; Leis, Jose F.; Warner, Steven L.; Bearss, David J.; Ghosh, Asish K.; Kay, Neil Elliot.

In: Oncotarget, Vol. 9, No. 98, 01.12.2018, p. 37173-37184.

Research output: Contribution to journalArticle

Sinha, S, Boysen, JC, Chaffee, KG, Kabat, BF, Slager, SL, Parikh, SA, Secreto, CR, Call, T, Shanafelt, TD, Leis, JF, Warner, SL, Bearss, DJ, Ghosh, AK & Kay, NE 2018, 'Chronic lymphocytic leukemia cells from ibrutinib treated patients are sensitive to Axl receptor tyrosine kinase inhibitor therapy', Oncotarget, vol. 9, no. 98, pp. 37173-37184.
Sinha, Sutapa ; Boysen, Justin C. ; Chaffee, Kari G. ; Kabat, Brian F. ; Slager, Susan L ; Parikh, Sameer A ; Secreto, Charla R. ; Call, Tim ; Shanafelt, Tait D. ; Leis, Jose F. ; Warner, Steven L. ; Bearss, David J. ; Ghosh, Asish K. ; Kay, Neil Elliot. / Chronic lymphocytic leukemia cells from ibrutinib treated patients are sensitive to Axl receptor tyrosine kinase inhibitor therapy. In: Oncotarget. 2018 ; Vol. 9, No. 98. pp. 37173-37184.
@article{02fea268baff43709a9a15e24c4a4fc2,
title = "Chronic lymphocytic leukemia cells from ibrutinib treated patients are sensitive to Axl receptor tyrosine kinase inhibitor therapy",
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 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.",
keywords = "Apoptosis, AXL, CLL, Ibrutinib, TP-0903",
author = "Sutapa Sinha and Boysen, {Justin C.} and Chaffee, {Kari G.} and Kabat, {Brian F.} and Slager, {Susan L} and Parikh, {Sameer A} and Secreto, {Charla R.} and Tim Call and Shanafelt, {Tait D.} and Leis, {Jose F.} and Warner, {Steven L.} and Bearss, {David J.} and Ghosh, {Asish K.} and Kay, {Neil Elliot}",
year = "2018",
month = "12",
day = "1",
language = "English (US)",
volume = "9",
pages = "37173--37184",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals",
number = "98",

}

TY - JOUR

T1 - Chronic lymphocytic leukemia cells from ibrutinib treated patients are sensitive to Axl receptor tyrosine kinase inhibitor therapy

AU - Sinha, Sutapa

AU - Boysen, Justin C.

AU - Chaffee, Kari G.

AU - Kabat, Brian F.

AU - Slager, Susan L

AU - Parikh, Sameer A

AU - Secreto, Charla R.

AU - Call, Tim

AU - Shanafelt, Tait D.

AU - Leis, Jose F.

AU - Warner, Steven L.

AU - Bearss, David J.

AU - Ghosh, Asish K.

AU - Kay, Neil Elliot

PY - 2018/12/1

Y1 - 2018/12/1

N2 - 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.

AB - 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.

KW - Apoptosis

KW - AXL

KW - CLL

KW - Ibrutinib

KW - TP-0903

UR - http://www.scopus.com/inward/record.url?scp=85058441649&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85058441649&partnerID=8YFLogxK

M3 - Article

VL - 9

SP - 37173

EP - 37184

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 98

ER -