TY - JOUR
T1 - Cholesterol esterification inhibition and imatinib treatment synergistically inhibit growth of BCR-ABL mutation-independent resistant chronic myelogenous leukemia
AU - Bandyopadhyay, Shovik
AU - Li, Junjie
AU - Traer, Elie
AU - Tyner, Jeffrey W.
AU - Zhou, Amy
AU - Oh, Stephen T.
AU - Cheng, Ji Xin
N1 - Funding Information:
This work was partially supported by a grant from Walther Cancer Foundation to JXC. This work was supported by NIH grant K08HL106576 to STO. Support for patient sample collection and processing was provided by NIH grant P01CA101937. Technical support was provided by the Alvin J. Siteman Cancer Center Tissue Procurement Core Facility, Flow Cytometry Core, and Immunomonitoring Laboratory, which are supported by NCI Cancer Center Support Grant P30CA91842. The Immunomonitoring Laboratory is also supported by the Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs. The authors thank C. Miner and O. Malkova for assistance with mass cytometry experiments.
Publisher Copyright:
© 2017 Bandyopadhyay et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2017/7
Y1 - 2017/7
N2 - Since the advent of tyrosine kinase inhibitors (TKIs) such as imatinib, nilotinib, and dasatinib, chronic myelogenous leukemia (CML) prognosis has improved greatly. However, ~30–40% of patients develop resistance to imatinib therapy. Although most resistance is caused by mutations in the BCR-ABL kinase domain, 50–85% of these patients develop resistance in the absence of new mutations. In these cases, targeting other pathways may be needed to regain clinical response. Using label-free Raman spectromicroscopy, we evaluated a number of leukemia cell lines and discovered an aberrant accumulation of cholesteryl ester (CE) in CML, which was found to be a result of BCR-ABL kinase activity. CE accumulation in CML was found to be a cancer-specific phenomenon as untransformed cells did not accumulate CE. Blocking cholesterol esterification with avasimibe, a potent inhibitor of acyl-CoA cholesterol acyltransferase 1 (ACAT-1), significantly suppressed CML cell proliferation in Ba/F3 cells with the BCR-ABLT315I mutation and in K562 cells rendered imatinib resistant without mutations in the BCR-ABL kinase domain (K562R cells). Furthermore, the combination of avasimibe and imatinib caused a profound synergistic inhibition of cell proliferation in K562R cells, but not in Ba/F3T315I. This synergistic effect was confirmed in a K562R xenograft mouse model. Analysis of primary cells from a BCR-ABL mutation-independent imatinib resistant patient by mass cytometry suggested that the synergy may be due to downregulation of the MAPK pathway by avasimibe, which sensitized the CML cells to imatinib treatment. Collectively, these data demonstrate a novel strategy for overcoming BCR-ABL mutation-independent TKI resistance in CML.
AB - Since the advent of tyrosine kinase inhibitors (TKIs) such as imatinib, nilotinib, and dasatinib, chronic myelogenous leukemia (CML) prognosis has improved greatly. However, ~30–40% of patients develop resistance to imatinib therapy. Although most resistance is caused by mutations in the BCR-ABL kinase domain, 50–85% of these patients develop resistance in the absence of new mutations. In these cases, targeting other pathways may be needed to regain clinical response. Using label-free Raman spectromicroscopy, we evaluated a number of leukemia cell lines and discovered an aberrant accumulation of cholesteryl ester (CE) in CML, which was found to be a result of BCR-ABL kinase activity. CE accumulation in CML was found to be a cancer-specific phenomenon as untransformed cells did not accumulate CE. Blocking cholesterol esterification with avasimibe, a potent inhibitor of acyl-CoA cholesterol acyltransferase 1 (ACAT-1), significantly suppressed CML cell proliferation in Ba/F3 cells with the BCR-ABLT315I mutation and in K562 cells rendered imatinib resistant without mutations in the BCR-ABL kinase domain (K562R cells). Furthermore, the combination of avasimibe and imatinib caused a profound synergistic inhibition of cell proliferation in K562R cells, but not in Ba/F3T315I. This synergistic effect was confirmed in a K562R xenograft mouse model. Analysis of primary cells from a BCR-ABL mutation-independent imatinib resistant patient by mass cytometry suggested that the synergy may be due to downregulation of the MAPK pathway by avasimibe, which sensitized the CML cells to imatinib treatment. Collectively, these data demonstrate a novel strategy for overcoming BCR-ABL mutation-independent TKI resistance in CML.
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U2 - 10.1371/journal.pone.0179558
DO - 10.1371/journal.pone.0179558
M3 - Article
C2 - 28719608
AN - SCOPUS:85024380404
VL - 12
JO - PLoS One
JF - PLoS One
SN - 1932-6203
IS - 7
M1 - e0179558
ER -