Cholesterol esterification inhibition and imatinib treatment synergistically inhibit growth of BCR-ABL mutation-independent resistant chronic myelogenous leukemia

Abstract

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.

Cholesterol metabolism in cancer: mechanisms and therapeutic opportunities

“…Developing inhibitors against CE is of high clinical interest (Table 1). In an imatinib-resistant chronic myelogenous leukaemia cell line, inhibition of CE by the ACAT1 inhibitor avasimibe suppresses tumour growth and subsequently restores imatinib sensitivity by downregulating MAPK signaling 110 . In prostate cancer, avasimibe treatment impairs the Wnt-β-catenin pathway and thus suppresses metastasis 111 .…”

Cholesterol esterification inhibition and gemcitabine synergistically suppress pancreatic ductal adenocarcinoma proliferation

“…Recent studies have identified an aberrant accumulation of cholesteryl ester (CE) mediated by the enzyme Acyl coenzyme A: cholesterol acyltransferase 1 (ACAT-1) in multiple cancers, including prostate, pancreatic, leukemia, glioma, breast, colon and lung cancer [ 16 – 22 ]. Inhibition of ACAT-1 using a small molecule inhibitor, avasimibe, effectively removed CE accumulation and suppressed tumor growth.…”

Bryonolic Acid Blocks Cancer Cell Clonogenicity and Invasiveness through the Inhibition of Fatty Acid: Cholesteryl Ester Formation

“…BrA was less potent than the prototypical ACAT inhibitor Sah 58-035 but more potent than two other pentacyclic terpenoids betulinic acid and ursolic acid that are well studied for their pharmacological properties [ 7 , 44 , 45 ]. Although ACAT inhibition was earlier used to screen compounds with steroidal backbones for putative antiatheromatous properties [ 31 ], recent data from the literature showed that cholesteryl esters of fatty acids displayed tumour promoter properties and that ACAT inhibition in cancer cells blocked cancer cell invasiveness and clonogenicity and activate the lymphocyte T CD8+ antitumor activity [ 13 , 18 , 27 , 29 , 30 , 35 , 36 ]. We report here for the first time that BrA displays ACAT inhibition and inhibits cancer cell clonogenicity and invasiveness.…”

“…These pathways include the oestrogen receptor alpha (ERα), cholesterol-5,6-epoxide hydrolase (ChEH) and acyl-co-A cholesterol acyl transferase (ACAT). The ACAT catalysed the esterification of cholesteryl esters with fatty acids and these fatty acid:cholesteryl esters were recently shown to act as tumour promoters making ACAT a new target in cancer research [ 13 , 18 , 25 , 27 , 28 , 29 , 30 ]. We report that BrA displayed anticancer properties through the inhibition of cholesterol esterification.…”