MLL-AF9 leukemias are sensitive to PARP1 inhibitors combined with cytotoxic drugs

Maifrede, Silvia; Martı́nez, Esteban; Nieborowska‐Skorska, Margaret; Marcantonio, Daniela Di; Hulse, Michael; Le, Bac Viet; Zhao, Huaqing; Piwocka, Katarzyna; Tempera, Italo; Sykes, Stephen M.; Skórski, Tomasz

doi:10.1182/bloodadvances.2017006247

Cited by 27 publications

(26 citation statements)

References 29 publications

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“…To conclude, the effects produced by ODC on blast proliferation, cell cycle and DNA damage levels mirrored the ones induced by CDR and daunorubicin regardless of the cell lines tested, but ODC generated gene expression patterns different from daunorubicin monotherapy and CDR. Our results show that NPM1-DNMT3A mutated AML is susceptible to the action of ODC in this in vitro setting and reinforce the reports that so does THP1, too (10). This phenomenon can be attributed to increased amounts of DSB, but also probably, to the effects of ODC on the expression of RAD51 and PARP1 genes on both cell lines.…”

supporting

confidence: 89%

DNMT3A-NPM1 mutated acute myeloid leukaemia shows sensitivity to a PARP1 inhibitor combined with daunorubicin in an in vitro model

Gafencu

Pileczki

Jurj

et al. 2018

Preprint

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Acute myeloid leukaemia is a neoplasia in need of new treatment approaches. PARP inhibitors are a class of targeted therapeutics for cancer that disrupts dysfunctional DNA damage response in various neoplasia. MLL-AF9 mutated leukaemias are sensitive to combinations of PARP inhibitors and cytotoxic drugs. Moreover, DNMT3A and NPM1 mutations are linked to dysfunctions in DNA damage response. Therefore, we investigated if DNMT3A-NPM1 mutated AML cell line is sensible to PARP inhibitors combined with anthracyclines. Our results show that DNMT3A-NPM1 mutated AML is as sensible to combinations of PARP inhibitors and anthracyclines as MLL-AF9 mutated leukaemias, in an in vitro setting.

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supporting

confidence: 89%

DNMT3A-NPM1 mutated acute myeloid leukaemia shows sensitivity to a PARP1 inhibitor combined with daunorubicin in an in vitro model

Gafencu

Pileczki

Jurj

et al. 2018

Preprint

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“…The effect of dual synthetic lethality may be triggered selectively in BRCA-deficient cells. MLL-AF9-positive leukemia cells are BRCA proficient, but they are sensitive to PARPi, especially when combined with standard cytotoxic drug ( Maifrede et al, 2017b ). However, these cells did not respond favorably to the combination of PARPi + RAD52i ( Figure S2B ), most likely because PARP1-dependent but not RAD52-mediated mechanisms play a major role in their DNA repair.…”

Section: Resultsmentioning

confidence: 99%

“…Clonogenic activity was assessed 7 days after plating of treated cells. Cell death and γ-H2AX staining were examined by flow cytometry after staining with Fixable Viability Dye eFluor 780 (eBioscience) and Alexa Fluor 647 anti-γ-H2AX (BD Biosciences) as described previously ( Maifrede et al, 2017b ). For long-term experiments, fresh inhibitors were added every 3–4 days, and cells were expanded in fresh medium every 7 days.…”

Section: Methodsmentioning

confidence: 99%

Simultaneous Targeting of PARP1 and RAD52 Triggers Dual Synthetic Lethality in BRCA-Deficient Tumor Cells

et al. 2018

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SUMMARY PARP inhibitors (PARPis) have been used to induce synthetic lethality in BRCA-deficient tumors in clinical trials with limited success. We hypothesized that RAD52-mediated DNA repair remains active in PARPi-treated BRCA-deficient tumor cells and that targeting RAD52 should enhance the synthetic lethal effect of PARPi. We show that RAD52 inhibitors (RAD52is) attenuated single-strand annealing (SSA) and residual homologous recombination (HR) in BRCA-deficient cells. Simultaneous targeting of PARP1 and RAD52 with inhibitors or dominant-negative mutants caused synergistic accumulation of DSBs and eradication of BRCA-deficient but not BRCA-proficient tumor cells. Remarkably, Parp1−/−; Rad52−/− mice are normal and display prolonged latency of BRCA1-deficient leukemia compared with Parp1−/− and Rad52−/− counterparts. Finally, PARPi+RAD52i exerted synergistic activity against BRCA1-deficient tumors in immunodeficient mice with minimal toxicity to normal cells and tissues. In conclusion, our data indicate that addition of RAD52i will improve therapeutic outcome of BRCA-deficient malignancies treated with PARPi.

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“…It is interesting to note that 2 of 3 patients who relapsed (#7, #15) had KMT2A mutation. KMT2A is a mixed lineage leukemia (MLL) transcriptional coactivator, also known as histone-lysine N-methyltransferase 2A (40). Leukemia-driven KMT2A fusions with dominant transactivation ability are reportedly proficient in DNA damage repair and insensitive to PARP inhibition (41, 42).…”

Section: Discussionmentioning

confidence: 99%

Final Report of a Phase I Trial of Olaparib with Cetuximab and Radiation for Heavy Smoker Patients with Locally Advanced Head and Neck Cancer

Karam

Reddy

Blatchford

et al. 2018

Clinical Cancer Research

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Our goal was to evaluate the safety and toxicity of combining a PARP inhibitor, olaparib, with cetuximab and fractionated intensity-modulated radiotherapy for patients with locally advanced head and neck cancer and heavy smoking histories. Patients with ≥10 packs/year history of smoking were treated with olaparib at doses ranging from 25-200 mg orally twice daily beginning approximately 10 days prior to initiation of and with concurrent radiation (69.3 Gy in 33 fractions) using a time-to-event continual reassessment method model. Cetuximab was administered starting approximately 5 days prior to radiation per standard of care. A total of 16 patients were entered onto the study, with 15 evaluable for acute toxicity. The most common treatment-related grade 3-4 side effects were radiation dermatitis and mucositis (38% and 69%, respectively). The MTD was determined to be 50 mg orally twice daily, but the recommended phase II dose was deemed to be 25 mg orally twice daily. At a median follow-up of 26 months, the actuarial median overall survival was 37 months, but was not reached for other endpoints. Two-year overall survival, progression-free survival, local control, and distant control rates were 72%, 63%, 72%, and 79%, respectively. Patients who continued to smoke during therapy experienced higher recurrence rates. and were identified as potential correlatives of response on gene amplification and mutational analysis. Olaparib at 25 mg orally twice daily with concurrent cetuximab and radiation was well tolerated with reduced dermatitis within the radiation field. Response rates were promising for this high-risk population. .

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MLL-AF9 leukemias are sensitive to PARP1 inhibitors combined with cytotoxic drugs

Abstract: Key Points PARP1 is required for the maintenance of MLL-AF9 leukemias. PARP1 inhibitors enhance the therapeutic effect of cytotoxic drugs against MLL-AF9 leukemias.

Cited by 27 publications

References 29 publications

DNMT3A-NPM1 mutated acute myeloid leukaemia shows sensitivity to a PARP1 inhibitor combined with daunorubicin in an in vitro model

DNMT3A-NPM1 mutated acute myeloid leukaemia shows sensitivity to a PARP1 inhibitor combined with daunorubicin in an in vitro model

Simultaneous Targeting of PARP1 and RAD52 Triggers Dual Synthetic Lethality in BRCA-Deficient Tumor Cells

Final Report of a Phase I Trial of Olaparib with Cetuximab and Radiation for Heavy Smoker Patients with Locally Advanced Head and Neck Cancer

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