Resistance to Dasatinib in primary chronic lymphocytic leukemia lymphocytes involves AMPK-mediated energetic re-programming

Abstract

Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults in the western world. Although promising new therapies for this incurable disease are being tested in clinical trials, the therapeutic relevance of metabolic rewiring in chronic lymphocytic leukemia (CLL) is poorly understood. The aim of this study was to identify targetable metabolic differences in primary CLL lymphocytes by the use of Dasatinib. Dasatinib is a multi-tyrosine kinase inhibitor used to treat chronic myelogenous leukemia (CML) and is being tested in clinical trials for several cancers including CLL. This drug has been shown to be beneficial to CML patients suffering from diabetes by reducing their glucose plasma levels. In keeping with this previous observation, we report that Dasatinib induced glucose use while reducing lactate production, suggesting that this tyrosine kinase inhibitor decreases aerobic glycolysis and shifts glucose use in primary CLL lymphocytes. Our results suggest that primary CLL lymphocytes (independently of traditional prognostic factors) can be stratified in two subsets by their sensitivity to Dasatinib in vitro. Increased glucose use induced by Dasatinib or by inhibition of mitochondrial respiration was not sufficient to sustain survival and ATP levels in CLL samples sensitive to Dasatinib. The two subsets of primary CLL lymphocytes are characterized as well by a differential dependency on mitochondrial respiration and the use of anabolic or catabolic processes to cope with induced metabolic/energetic stress. Differential metabolic reprogramming between subsets is supported by the contrasting effect on the survival of Dasatinib treated CLL lymphocytes with pharmacological inhibition of two master metabolic regulators (mTorc1 and AMPK) as well as induced autophagy. Alternative metabolic organization between subsets is further supported by the differential basal expression (freshly purified lymphocytes) of active AMPK, regulators of glucose metabolism and modulators of AKT signaling. The contrasting metabolic features revealed by our strategy could be used to metabolically target CLL lymphocyte subsets creating new therapeutic windows for this disease for mTORC1 or AMPK inhibitors. Indeed, we report that Metformin, a drug used to treat diabetes was selectively cytotoxic to Dasatinib sensitive samples. Ultimately, we suggest that a similar strategy could be applied to other cancer types by using Dasatinib and/or relevant tyrosine kinase inhibitors.

B-cell Receptor Signaling Regulates Metabolism in Chronic Lymphocytic Leukemia

“…Additionally, free oxygen radicals in cells are heterogeneous among patients with CLL but significantly higher in CLL cells from patients with prior chemotherapy (24). CLL bioenergetic rewiring is also associated with kinase sensitivity; for example, CLL was classified into subsets based on the dasatinib-induced differential dependency on mitochondrial respiration to cope with cellular stress and meet the ATP demands (25). …”

High-content screening identifies kinase inhibitors that overcome venetoclax resistance in activated CLL cells

“…The drug concentrations tested in our validation studies were in the range of clinically achievable concentrations for each of the KIs, with achievable plasma concentrations of 0.25 mM, 0.5 mM, and up to 1.1 mM reported for sunitinib, [56][57][58][59][60] ibrutinib (NCT01105247), 66 and idelalisib (NCT00710528, NCT01090414), 48 respectively. P16 P17 P18 P19 P20 P21 P22 P23 P24 P25 P26 P27 P16 P17 P18 P19 P20 P21 P22 P23 P24 P25 P26 P27 P16 P17 P18 P19 P20 P21 P22 P23 P24 P25 P26 P27 sunitinib Other KIs such as dasatinib [67][68][69][70][71] and flavoperidol [72][73][74] were identified as having a high total kill with venetoclax ( Figure 3A, arrow and arrowhead, respectively). In combination with venetoclax in vitro, dasatinib ranked in position 10 of 31 licensed drugs and its venetoclax-enhanced effect was intermediate and detected in only 5 of 13 patients ( Figure 3A-B, arrow).…”

Altered glutamine metabolism in platinum resistant ovarian cancer

“…In ovarian cancer, platinum resistance has also been associated with an increase in stem-like properties mediated by upregulated Wnt signaling [24] and differential expression of microRNAs such as miR-181a [30]. More recently several studies have highlighted the importance of altered glucose or fatty acid metabolism in mediating resistance to chemotherapy or targeted therapies [31–38]. Despite increased knowledge about the biology of platinum resistance, improved therapy in ovarian cancer has been lacking due to the complexity of the mechanisms involved and cross-talk and redundancy of governing signaling pathways [39, 40].…”