Abstract
To the editor,
Histone deacetylase inhibitors (HDACis) have been explored since the early 2000s with notable success in treating certain lymphomas, which led to FDA approval for cutaneous T-cell lymphoma in 2006. 1 The recent article by Xiao et al. has broadly reviewed the role of HDACis in acute leukemia (AL). 2 However, it appears that the most important barrier in the routine clinical implementation of these agents may have been overlooked and remained underexplored. Despite preclinical success in leukemic models, the efficacy of HDACis in clinical settings remains limited, primarily due to resistance development. The latest studies have suggested combination therapies pairing HDACis with agents targeting complementary pathways—such as apoptotic regulators or DNA methyltransferase (DNMT) inhibitors—to enhance sensitivity and counteract resistance in AL. 3 Here, we address the molecular and cellular mechanisms and pathways contributing to HDACi resistance in AL.
Epigenetic compensation and redundant pathways
HDACis primarily target histone acetylation to promote chromatin relaxation and gene transcription. AL cells, however, can activate redundant pathways to maintain their malignant state. Compensatory upregulation of alternative epigenetic modifications, such as DNA methylation and histone methylation, can counteract the effects of HDACis by re-silencing tumor suppressor genes. For instance, increased DNMT activity can restore gene silencing in leukemic cells, evading HDACi-induced acetylation. Preclinical and early clinical studies have highlighted the efficacy of combining HDACis with DNMTis, such as azacitidine or decitabine, suggesting that dual inhibition may prevent re-silencing of critical tumor suppressor genes through a sustained epigenetic reprogramming that AL cells cannot easily bypass, potentially improving patient outcomes. 4
Overexpression of efflux pumps
A chief barrier in treating AL with HDACi is drug efflux mediated by adenosine triphosphate-binding cassette (ABC) transporters. These transmembrane proteins actively contribute to reducing intracellular HDACi concentrations, thus limiting their efficacy. Overexpression of ABC transporters such as ABCB1 (P-glycoprotein) and ABCC1 (multidrug resistance-associated protein 1) has been implicated in HDACi resistance. 5 Clinical trials combining HDACis with ABC transporter inhibitors or alternative drug delivery methods, such as nanoparticle formulations, are currently under investigation.
Compensatory signaling pathways
In response to HDACi-induced cellular stress, AL cells activate compensatory signaling pathways that promote survival and reduce sensitivity to apoptosis. Notably, the PI3K/AKT/mTOR and MAPK pathways are upregulated in HDACi-resistant cells, promoting cell survival and proliferation despite HDACi treatment. 6 Preclinical evidence is in favor of increasing HDACi efficacy through the inhibition of these pathways.
Altered expression of pro- and antiapoptotic genes
Resistance to HDACis often arises when AL cells adapt by upregulating the expression of antiapoptotic BCL-2, BCL-XL, or MCL-1. Downregulation of key pro-apoptotic genes like BAX and BAK reduces the leukemic cells’ responsiveness to HDACis. Small-molecule inhibitors of anti-apoptotic proteins, such as the BCL-2 inhibitor venetoclax, are being explored as potential combinatory agents with HDACis. 7
Epigenetic plasticity and cancer stem cells
Cancer stem cells (CSCs) exhibit significant epigenetic plasticity, enabling them to dynamically adapt to therapeutic pressure. CSCs in AL can survive HDACi treatment through reversible changes in gene expression that allow them to re-establish the leukemic cell population after drug withdrawal. This plasticity, combined with an ability to undergo quiescence, enables CSCs to evade HDACi-induced cell death and subsequently re-initiate leukemia. Although still under investigation, CSC-targeting agents, such as those involving Notch or Wnt signaling, may help eliminate CSCs when used in conjunction with HDACis. 8 Additionally, maintenance therapy with HDACis or other epigenetic modulators may prevent CSC-driven relapse in AL.
Table 1 summarizes the latest studies documenting clinical resistance to HDACis in AL patients. Future studies should focus on developing new generations of HDACis with improved selectivity and exploring combination regimens with potential efficacy enhancers, such as DNMTis and efflux pump inhibitors. Overcoming HDACi resistance holds the potential to transform the therapeutic landscape for patients with AL in the near future.
Summary of early trials documenting clinical resistance to histone deacetylase inhibitors in acute leukemia.
ABL, acute biphenotypic leukemia; ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; DCAG, decitabine, cytarabine, aclarubicin, and granulocyte colony-stimulating factor; MDS, myelodysplastic syndrome.
