Abstract
Simple SummaryVenetoclax is an antagonist of the antiapoptotic protein Bcl-2, and is currently approved for treatment of chronic lymphocytic leukemia (CLL). Recently, clinical use has shown that patients develop resistance to venetoclax. Therefore, the demand for novel targets for treatment of CLL remains high. One such target is autophagy, an evolutionarily old system for degradation of long-lived proteins and organelles that recovers the energy for normal cellular functions. Here, the antileukemic potential of different autophagy inhibitors was evaluated in patient-derived CLL cells. Among these, inhibitors of the AMPK/ULK1 pathway and late-stage autophagy were the most potent, with selective cytotoxic activities seen. They also show activity against CLL cells with unfavorable genetic characteristics. These inhibitors complement the cytotoxic action of venetoclax. In conclusion, targeting autophagy shows potential as a novel approach for treatment of patients with CLL.Continuous treatment of patients with chronic lymphocytic leukemia (CLL) with venetoclax, an antagonist of the anti-apoptotic protein Bcl-2, can result in resistance, which highlights the need for novel targets to trigger cell death in CLL. Venetoclax also induces autophagy by perturbing the Bcl-2/Beclin-1 complex, so autophagy might represent a target in CLL. Diverse autophagy inhibitors were assessed for cytotoxic activities against patient-derived CLL cells. The AMPK inhibitor dorsomorphin, the ULK1/2 inhibitor MRT68921, and the autophagosome–lysosome fusion inhibitor chloroquine demonstrated concentration-dependent and time-dependent cytotoxicity against CLL cells, even in those from hard-to-treat patients who carried del(11q) and del(17p). Dorsomorphin and MRT68921 but not chloroquine triggered caspase-dependent cell death. According to the metabolic activities of CLL cells and PBMCs following treatments with 10 µM dorsomorphin (13% vs. 84%), 10 µM MRT68921 (7% vs. 78%), and 25 µM chloroquine (41% vs. 107%), these autophagy inhibitors are selective toward CLL cells. In these CLL cells, venetoclax induced autophagy, and addition of dorsomorphin, MRT68921, or chloroquine showed potent synergistic cytotoxicities. Additionally, MRT68921 alone induced G2 arrest, but when combined with venetoclax, it triggered caspase-dependent cytotoxicity. These data provide the rationale to target autophagy and for autophagy inhibitors as potential treatments for patients with CLL.
Highlights
Over the last decade, the treatment of patients with chronic lymphocytic leukemia (CLL) has undergone a radical change that has led to the advent of targeted therapies.Among the novel targeted therapies, venetoclax is a first-in-class antagonist of the antiapoptotic protein B-cell lymphoma 2 (Bcl-2)
We showed that all three autophagy inhibitors acted against cells carrying del(11q) or del(17p), evidencing that inhibition of autophagy is as effective in CLL cells with unfavorable genetic characteristics as in cells with favorable genetic characteristics with the exception of MRT68921, which turned out to be more effective in cells with unmutated immunoglobulin heavy-chain variable region (IGHV) (p = 0.0266) (Figure 2b)
As lysosomes are an integral part of the autophagic process [27], and autophagic inhibitors can indirectly or directly affect the physiological role of lysosomes in the autophagic process, we investigated their integrity after exposure of patient-derived CLL cells to these autophagy inhibitors
Summary
The treatment of patients with chronic lymphocytic leukemia (CLL) has undergone a radical change that has led to the advent of targeted therapies.Among the novel targeted therapies, venetoclax is a first-in-class antagonist of the antiapoptotic protein B-cell lymphoma 2 (Bcl-2). The implications for targeting autophagy in cancer treatments remain controversial This is due to both the cell-type-dependent and context-dependent functions, and their duality in cellular homeostasis, as autophagy is both a prosurvival pathway and a form of programmed cell death [5,6,7,8]. A mere handful of studies have touched on the role of autophagy in CLL, both from the prognostic point of view and for possible implications in therapy The latter is of particular interest, as initial autophagy signaling pathways are well intertwined with the BCR signaling pathway. Another study reported that the mTOR inhibitor CC-115 can reverse CD40-mediated resistance of CLL cells to venetoclax, through blocking CD40-induced Mcl-1 and Bcl-xL up-regulation, suggesting a role for mTOR in the control of the Bcl-2 family of proteins [12]. The Bcl-2/Beclin-1 complex physically and functionally links autophagy and apoptosis, which proposes that Bcl-2 antagonists (such as venetoclax) can affect both systems at once
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