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Repression of DNA Damage Response Sensitizes APL Cells to the Combined Genotoxicity of All-Trans Retinoic Acid and Arsenic Trioxide

ABSTRACT: The synergistic combination of All-Trans Retinoic Acid (ATRA) and Arsenic Trioxide (ATO) has transformed acute promyelocytic leukemia (APL) from a terminal disease into a curable one. However, the molecular basis for the APL-specific synergy remains to be fully defined. In this work, we studied the mechanism that drives the unique efficacy of ATRA/ATO on APL cells. We found that the ATRA/ATO combination generates a high level of endogenous genotoxic stress, leading to exacerbated accumulation of DNA damage in APL cellular models and patient samples. Crucially, we found that ATRA-treatment triggers the ubiquitin-proteasome -mediated degradation of key DNA damage response proteins, including ATM and FANCD2. This APL-specific event is independent of PML-RARA turnover and creates a profound vulnerability to genotoxic stress, rendering APL cells more susceptible to the combined genotoxic stress from the ATRA-ATO combination. Our findings reveal that the synergized induction of genotoxic stress and the concurrent impairment of the DNA damage response mechanisms constitute a lethal "Double-Hit" that promotes APL-specific apoptosis. This study provides a novel paradigm for understanding therapeutic synergy and suggests that targeting DDR protein stability may extend the success of differentiation therapy to a broader range of leukemia.

ORGANISM(S): Homo Sapiens

SUBMITTER: Lei Li

PROVIDER: PXD078309 | iProX | Wed May 13 00:00:00 BST 2026

REPOSITORIES: iProX

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Repression of DNA Damage Response Sensitizes APL Cells to the Combined Genotoxicity of All-Trans Retinoic Acid and Arsenic Trioxide

Project description:The synergistic combination of All-Trans Retinoic Acid (ATRA) and Arsenic Trioxide (ATO) has transformed acute promyelocytic leukemia (APL) from a terminal disease into a curable one. However, the molecular basis for the APL-specific synergy remains to be fully defined. In this work, we studied the mechanism that drives the unique efficacy of ATRA/ATO on APL cells. We found that the ATRA/ATO combination generates a high level of endogenous genotoxic stress, leading to exacerbated accumulation of DNA damage in APL cellular models and patient samples. Crucially, we found that ATRA-treatment triggers the ubiquitin-proteasome -mediated degradation of key DNA damage response proteins, including ATM and FANCD2. This APL-specific event is independent of PML-RARA turnover and creates a profound vulnerability to genotoxic stress, rendering APL cells more susceptible to the combined genotoxic stress from the ATRA-ATO combination. Our findings reveal that the synergized induction of genotoxic stress and the concurrent impairment of the DNA damage response mechanisms constitute a lethal "Double-Hit" that promotes APL-specific apoptosis. This study provides a novel paradigm for understanding therapeutic synergy and suggests that targeting DDR protein stability may extend the success of differentiation therapy to a broader range of leukemia.

2026-05-16 | GSE330966 | GEO

Gemcitabine and ATR inhibitors synergize to kill PDAC cells by blocking DNA damage response

Project description:The DNA-damaging agent gemcitabine (GEM) is a first-line treatment for pancreatic cancer but chemoresistance is frequently observed. Several clinical trials investigate the efficacy of GEM in combination with targeted drugs including kinase inhibitors but the experimental evidence for such rational is often unclear. Here, we phenotypically screened 13 human pancreatic adenocarcinoma (PDAC) cell lines against GEM in combination with 140 clinical kinase inhibitors and observed strong synergy for the ATR inhibitor Elimusertib in most cell lines. Dose-dependent phosphoproteome profiling of four ATR inhibitors following DNA damage induction by GEM revealed a strong block of the DNA damage response pathway including phosphorylated pS468 of CHEK1 as the underlying mechanism of drug synergy. The current work provides a strong rationale for why the combination of GEM and ATR inhibition may be useful for the treatment of PDAC patients and constitutes a rich phenotypic and molecular resource for further investigating effective drug combinations.

2024-03-18 | MSV000094340 | MassIVE

Synergistic Potential of CDK4/6 Inhibitors and ATRA in non-APL AML.

Project description:Background: Acute myeloid leukemia (AML) is a heterogeneous disease characterized by diverse genetic abnormalities. The standard of care remains to be chemotherapy and stem cell transplantation. In acute promyelocytic leukemia (APL), differentiation therapy with all-trans retinoic acid (ATRA) has significantly improved outcomes. Despite this, the success of ATRA has yet to be transferred to non-APL AML. Exploring combinations to enhance the efficacy of ATRA in non-APL AML remains a key focus. Objective: To investigate the therapeutic effect of ATRA in combination with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in non-APL AML. Methods: Non-APL AML cells and primary patient samples were treated with ATRA and CDK4/6 inhibitors. Key outcomes included differentiation, proliferation, cell viability, and colony-forming capacity. Combination synergy was evaluated, and gene expression analysis identified pathways associated with therapeutic effects. Results: The combination demonstrated dose-dependent effects, enhancing differentiation and reducing proliferation, cell viability, and colony-forming capacity. A synergistic effect was observed across AML cell lines. Gene expression profiling revealed the co-regulation of differentiation-associated genes, unveiling the mechanisms driving therapeutic synergy. Conclusion: Combination of CDK4/6 inhibitors with ATRA shows potential for differentiation-based AML treatment. This approach offers a promising avenue for improved outcomes in non-APL AML.

2025-03-18 | GSE291868 | GEO

PARP1 expression predicts and determines synergy between PARP1 inhibitors and trabectedin.

Project description:Trabectedin is a DNA-damaging agent with a peculiar mechanism of action; it traps the DNA repair machinery leading to DNA single- and double-strand breaks, particularly in BRCA1/2-deficient tumors. We hypothesized that trabectedin-induced DNA damage might activate PARP1 (a DNA-repair machinery key player), and consequently, PARP1 inhibition would perpetuate trabectedin-induced DNA damage. In several tumor histotypes, we demonstrated a different degree of synergism between trabectedin and PARP1 inhibitors (PARP1-Is). Independent of BRCA1/2 status, PARP1 expression dictated the degree of synergism. Namely, silenced PARP1 reduced trabectedin-PARP1-Is synergism, whereas overexpressed PARP1 increased combination efficacy. High-PARP1 expression and specific gene signatures associated with DNA damage response and repair (DDR-R) were predictive of trabectedin+PARP1-I synergy. These findings pave the way for the clinical development of this novel combination therapy, as well as evaluation of PARP1 expression and DDR-R signatures in tumor samples as predictive biomarkers of response.

2017-06-12 | GSE76981 | GEO

PARP1 expression drives the synergy between trabectedin and PARP1 inhibitors

2017-06-12 | GSE77175 | GEO

Combination treatmetn of MRT68921 and all-trans retinoic acid in HL-60 human leukemia cells

Project description:It was previously reported that inhibition of autophagosome formation by MRT68921 induced accumulation of cytosolic dsDNA, which can activate cytosolic DNA-sensor signaling pathway, thereby reducing cell viability through reactive oxygen species generation in leukemia cells. Thus, we examined the effect of combination treatment of MRT68921 and a leukemia differentiation therapeutic drug, all-trans retinoic acid.

2024-03-05 | GSE193056 | GEO

Cell specific models reveal conformation-specific RAF inhibitor combinations that synergistically inhibit ERK signaling in pancreatic cancer cells

Project description:Pancreatic ductal adenocarcinoma (PDAC) presents significant challenges for targeted clinical interventions due to prevalent KRAS mutations, rendering PDAC resistant to RAF and MEK inhibitors (RAFi and MEKi). In addition, responses to targeted therapies vary between patients. Here, we explored the differential sensitivities of PDAC cell lines to RAFi and MEKi and developed an isogenic pair comprising the most sensitive and resistant PDAC cells. To simulate patient or tumor specific variations, we constructed cell line-specific mechanistic models based on protein expression profiling and differential properties of KRAS mutants. These models predicted synergy between two RAFi with different conformation specificity (type I½ and type II RAFi) in inhibiting ppERK and reducing PDAC cell viability. This synergy was experimentally validated across all four studied PDAC cell lines. Our findings underscore the need for combination approaches to inhibit the ERK pathway in PDAC.

2024-09-03 | PXD047912 | Pride

Solubility based mechanistic profiling of combinatorial drug therapy

Project description:Acute myeloid leukemia (AML) poses a major clinical challenge due to its genetic diversity, relapse rates, and chemotherapy toxicity. While rational drug combinations improve efficacy, their mechanisms remain poorly understood. We introduce CoPISA (Proteome Integral Solubility/Stability Alteration Analysis for Combinations), a high-throughput proteomics workflow that identifies protein solubility/stability changes unique to drug combinations. Applied to two AML drug pairs—LY3009120-sapanisertib (LS) and ruxolitinib-ulixertinib (RU)—CoPISA mapped protein targets in lysates and living cells. The analysis revealed a novel principle, “conjunctional targeting”, where drug pairs induce unique, cooperative effects not seen with individual drugs, akin to an AND-gate logic. LS-specific targets involved SUMOylation, chromatin condensation, and VEGF-linked adhesion; RU-specific targets disrupted DNA damage checkpoints, mitochondrial function, and RNA splicing, suggesting synthetic-lethal vulnerabilities. Post-translational modification profiling confirmed combination-induced changes (e.g., acetylation, dimethylation, phosphorylation) on key AML proteins like NPM1. Network analysis showed many targets were unique to combinations, including frequently mutated drivers DNMT3A, NPM1, and TP53. CoPISA reveals how drug pairs exert multi-axis pressure on AML cells, offering a mechanistic layer beyond classical synergy and guiding precision therapy design for AML and other complex cancers.

2026-02-12 | PXD066812 | Pride

Cell context is the third axis of synergy for ATR inhibition and cisplatin in Ewing sarcoma

Project description:Purpose: The importance of cellular context to the synergy of DNA Damage Response (DDR) targeted agents is important for tumors with mutations in DDR pathways, but less well-established for tumors driven by oncogenic transcription factors. In this study, we exploit the widespread transcriptional dysregulation of the EWS-FLI1 transcription factor to identify an effective DDR targeted combination therapy for Ewing Sarcoma (ES). Experimental Design: We used matrix drug screening to evaluate synergy between a DNA-PK inhibitor (M9831) or an ATR inhibitor (berzosertib) and chemotherapy. The combination of berzosertib and cisplatin was selected for broad synergy, mechanistically evaluated for ES selectivity, and optimized for in vivo schedule. Results: Berzosertib combined with cisplatin demonstrates profound synergy in multiple ES cell lines at clinically achievable concentrations. The synergy is due to loss of expression of the ATR downstream target CHEK1, loss of cell cycle checkpoints, and mitotic catastrophe. Consistent with the goals of the project, EWS-FLI1 drives the expression of CHEK1 and five other ATR pathway members. The loss of expression is not due to transcriptional repression and instead caused by degradation coupled with suppression of protein translation. The profound synergy is realized in vivo with a novel optimized schedule of this combination in subsets of ES models leading to durable complete responses in 50% of animals bearing two different ES xenografts. Conclusions: These data exploit EWS-FLI1 driven alterations in cell context to broaden the therapeutic window of berzosertib and cisplatin to establish a promising combination therapy and a novel in vivo schedule.

2024-03-13 | GSE260602 | GEO

mRNA gene expression profiling in a human AML cell line treated with small molecule inhibitors that impact different RNA polymerase transcription complexes, or their combination, in comparison to a global DNA-damaging anthracycline compound

Project description:Our results confirmed that CX-5461, a Pol I inhibitor, does not significantly impact mRNA expression at 6 hrs, while I-BET151 alone, known to inhibit MYC and expression of other oncognes, resulted in widespread changes in select gene expression programs as previously demonstrated (Dawson et al., 2011). Interestingly, the combination of CX-5461 and I-BET151 demonstrated no further gene expression changes from I-BET151 alone, suggesting that their mechanism of synergy is more likely directly associated with the CX-5461-mediated DNA damage response. Further, the mRNA gene expression changes following drug combination treatment are distinct from those following doxorubicin treatment, supporting that the synergistic effects of the novel combination of CX-5461 and I-BET151 do not rely on global DNA damage.

2019-08-26 | GSE118565 | GEO

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