A Novel ACLY Inhibitor Induces Transcriptional and Metabolic Reprogramming to Overcome Tyrosine kinase inhibitor Resistance in Lymphoma
VCB1, a novel ACLY inhibitor, shows promise in suppressing lymphoma growth in TKI-sensitive and resistant models, but further research is needed to confirm its clinical applicability.
Where it sits
this study against the rest of the glutathione (gsh) corpusSummary and findings
This study evaluated the novel ACLY inhibitor VCB1 in T-cell lymphoma models. The inhibitor demonstrated varying IC₅₀ values against different cell lines, indicating its potential to suppress lymphoma cell growth. Notably, VCB1 showed an IC₅₀ of 0.299 uM in TKI-sensitive SUPM2 and 1.62 uM in lorlatinib-resistant SUPM2-LR1000 cells.
Abstract
<h4>Background: </h4> Metabolic plasticity contributes to therapeutic resistance in T-cell lymphoma, but the metabolic dependencies underlying tyrosine kinase inhibitor (TKI) resistance remain poorly understood. ATP citrate lyase (ACLY), which converts citrate to cytosolic acetyl-CoA, links glucose metabolism to lipogenesis and acetylation-dependent regulation. We hypothesized that ACLY represents an actionable metabolic vulnerability in lymphoma. <h4>Methods:</h4> Structure-guided drug discovery and biochemical screening were used to identify the novel ACLY inhibitor VCB1. VCB1 was evaluated against recombinant human ACLY and in TKI-sensitive and TKI-resistant lymphoma models. Antitumor activity was assessed by proliferation, cell-cycle analysis, apoptosis, and immunoblotting, followed by integrated transcriptomic, metabolomic, and lipidomic profiling. <h4>Results:</h4> Our xenograft study showed that ACLY dependence in ALK+ALCL. We discovered novel ACLY inhibitor VCB1 directly inhibited recombinant ACLY with uM potency (IC₅₀, 0.9 uM) and strongly suppressed lymphoma cell growth. In ALK inhibitor-sensitive SUPM2, VCB1 showed an IC₅₀ of 0.299 uM and retained potency in lorlatinib-resistant SUPM2-LR1000 cells (1.62 uM), whereas BMS-303141 was substantially less active (17.46 and 22.07 uM). VCB1 similarly inhibited BTK inhibitor sensitive and resistant mantle cell lymphoma cell growth (IC₅₀, 0.28 and 0.278 uM), compared with BMS-303141 (30.5 and 37.01 uM). Multi-omics profiling revealed suppression of de novo lipogenesis, including ACACA, FASN, and PPARGC1B, together with extensive remodeling of triglyceride, phospholipid, cardiolipin, ceramide, and acylcarnitine species and increased expression of fatty-acid oxidation genes. VCB1 activated the integrated stress response (ISR), inducing ATF4, PPP1R15A, DDIT3, DDIT4 and SESN2, while disrupting purine and pyrimidine metabolism and reducing nucleotide biosynthetic genes, including CAD, DHODH, UCK2, and ATIC. VCB1 further activated an ACLY/ISR/CHAC1 axis associated with reduced GCLC/GCLM expression, glutathione depletion, and a decreased GSH/GSSG ratio, indicating impaired redox homeostasis. TKI-resistant cells exhibited distinct lipid-metabolic remodeling consistent with metabolic plasticity. VCB1 also altered immune-regulatory programs involving PDCD1, TIGIT, CD247, CD226, NFATC2, and inflammatory cytokines. Functionally, VCB1 induced cell cycle arrest and apoptosis. <h4>Conclusions:</h4> ACLY represents an integrated metabolic and signaling vulnerability in lymphoma. VCB1 suppresses lymphoma growth across TKI-sensitive and resistant models by disrupting lipid and nucleotide metabolism, metabolic adaptation and ISR and redox homeostasis supporting ACLY inhibition as a therapeutic strategy for TKI-resistant lymphoma.
Background
This paper addresses the metabolic vulnerabilities contributing to resistance against tyrosine kinase inhibitors (TKIs) in T-cell lymphoma. Previous research has indicated that metabolic plasticity plays a role in therapeutic resistance, but the specific mechanisms remain unclear. The study investigates ATP citrate lyase (ACLY) as a potential target for overcoming TKI resistance, which could provide insights into new therapeutic strategies.
Methods
The study utilized structure-guided drug discovery to identify VCB1 as a novel ACLY inhibitor. VCB1 was tested against recombinant human ACLY and in both TKI-sensitive and TKI-resistant lymphoma models. The primary outcomes measured included cell proliferation, apoptosis, and metabolic profiling, with a focus on lipid and nucleotide metabolism.
Results
The primary endpoint showed that VCB1 had an IC₅₀ of 0.299 µM in TKI-sensitive SUPM2 cells and retained activity in TKI-resistant SUPM2-LR1000 cells with an IC₅₀ of 1.62 µM. VCB1 also demonstrated significant inhibition of cell growth in mantle cell lymphoma, with IC₅₀ values of 0.28 µM and 0.278 µM for sensitive and resistant cells, respectively. The study reported a decrease in the GSH/GSSG ratio, indicating impaired redox homeostasis.
Interpretation
The findings suggest that VCB1 effectively inhibits ACLY and alters metabolic pathways in lymphoma cells, which is consistent with the role of ACLY in metabolic adaptation. While the statistical significance of the results is clear, the clinical relevance remains uncertain due to the preclinical nature of the study and the potential for small effect sizes. The study's reliance on in vitro and xenograft models introduces confounding factors that may limit the applicability of the results to human patients.
Key findings
- IC₅₀ of VCB1 in ALK inhibitor-sensitive SUPM2 was 0.299 µM.
- IC₅₀ of VCB1 in lorlatinib-resistant SUPM2-LR1000 cells was 1.62 µM.
- IC₅₀ of VCB1 in BTK inhibitor-sensitive mantle cell lymphoma was 0.28 µM.
- IC₅₀ of VCB1 in BTK inhibitor-resistant mantle cell lymphoma was 0.278 µM.
- IC₅₀ of BMS-303141 in SUPM2 was 17.46 µM and in SUPM2-LR1000 was 22.07 µM.
- GSH/GSSG ratio was decreased, indicating impaired redox homeostasis.
Limitations
- preclinical study, not human data
- reliance on in vitro and xenograft models
- potential small effect sizes not clinically meaningful
- single-site study may limit generalizability