Low dose DNA methyltransferase inhibitors potentiate PARP inhibitors in homologous recombination repair deficient tumors
Abstract Background Poly (ADP-Ribose) polymerase inhibitors are approved for treatment of tumors with BRCA1/2 and other homologous recombination repair (HRR) mutations. However, clinical responses are often not durable and treatment may be detrimental in advanced cancer due to excessive toxicities....
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BMC
2025-01-01
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| Series: | Breast Cancer Research |
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| Online Access: | https://doi.org/10.1186/s13058-024-01954-y |
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| author | Romain Pacaud Scott Thomas Sibapriya Chaudhuri Ann Lazar Luika A. Timmerman Pamela N. Munster |
| author_facet | Romain Pacaud Scott Thomas Sibapriya Chaudhuri Ann Lazar Luika A. Timmerman Pamela N. Munster |
| author_sort | Romain Pacaud |
| collection | DOAJ |
| description | Abstract Background Poly (ADP-Ribose) polymerase inhibitors are approved for treatment of tumors with BRCA1/2 and other homologous recombination repair (HRR) mutations. However, clinical responses are often not durable and treatment may be detrimental in advanced cancer due to excessive toxicities. Thus we are seeking alternative therapeutics to enhance PARP-directed outcomes. In an effort to expand the clinical use of PARP inhibitors to HRR proficient tumors, several groups have tested combinations of DNA methyltransferase inhibitors and PARP inhibitors. While this approach attenuated tumor cell proliferation in preclinical studies, subsequent clinical trials revealed little benefit. We hypothesized that benefit for this drug combination would only be specific to HRR deficient tumors, due to their inability to enact high fidelity DNA repair with subsequent cell death. Methods We generated hypomorphic BRCA1 and BRCA2 variants of the HRR proficient triple negative breast cancer cell line MDA-MB-231. We compared therapeutic response features such as RAD51 focus formation, cell cycle fraction alterations, DNA damage accumulation, colony formation, and cell death of these and other cell lines with and without intrinsic BRCA1/2 mutations. Results were confirmed in BRCA1/2 intact and deficient xenografts and PDX. Results Our targeted variants and cells with intrinsic BRCA1/2 mutations responded to low dose combination therapeutic treatment by G2M stalling, compounded DNA damage, severely attenuated colony formation, and importantly, increased cell death. In contrast, the parental MDA-MB-231 cells and other HRR proficient cell lines produced smaller cell populations with short term treatment, but with much less cumulative DNA damage, and minimal cell death. In animal studies, our BRCA-engineered hypomorphs and several independent PDX models with clinically relevant BRCA mutations were acutely more vulnerable to this drug combination. Conclusions We conclude that low dose DNA methyltransferase inhibition can cooperate with low dose PARP inhibition to increase DNA damage predominantly in cells with HRR deficiencies, ultimately producing more cell death than in HRR proficient tumors. We predict that clinical benefit will more likely be apparent in patients with DNA repair defective tumors and are focusing clinical exploration of this drug combination in these patients, with the goals of enhancing tumor cell death at minimal toxicities. |
| format | Article |
| id | doaj-art-0fe24e16ab974c51b3dc53369f619926 |
| institution | Kabale University |
| issn | 1465-542X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Breast Cancer Research |
| spelling | doaj-art-0fe24e16ab974c51b3dc53369f6199262025-01-19T12:44:08ZengBMCBreast Cancer Research1465-542X2025-01-0127111510.1186/s13058-024-01954-yLow dose DNA methyltransferase inhibitors potentiate PARP inhibitors in homologous recombination repair deficient tumorsRomain Pacaud0Scott Thomas1Sibapriya Chaudhuri2Ann Lazar3Luika A. Timmerman4Pamela N. Munster5Department of Medicine (Hematology/Oncology), School of Medicine, University of California San FranciscoDepartment of Medicine (Hematology/Oncology), School of Medicine, University of California San FranciscoDepartment of Medicine (Hematology/Oncology), School of Medicine, University of California San FranciscoDivision of Oral Epidemiology and Division of Biostatistics, School of Dentistry and School of Medicine, University of California San FranciscoHelen Diller Family Comprehensive Cancer Center, University of California San FranciscoDepartment of Medicine (Hematology/Oncology), School of Medicine, University of California San FranciscoAbstract Background Poly (ADP-Ribose) polymerase inhibitors are approved for treatment of tumors with BRCA1/2 and other homologous recombination repair (HRR) mutations. However, clinical responses are often not durable and treatment may be detrimental in advanced cancer due to excessive toxicities. Thus we are seeking alternative therapeutics to enhance PARP-directed outcomes. In an effort to expand the clinical use of PARP inhibitors to HRR proficient tumors, several groups have tested combinations of DNA methyltransferase inhibitors and PARP inhibitors. While this approach attenuated tumor cell proliferation in preclinical studies, subsequent clinical trials revealed little benefit. We hypothesized that benefit for this drug combination would only be specific to HRR deficient tumors, due to their inability to enact high fidelity DNA repair with subsequent cell death. Methods We generated hypomorphic BRCA1 and BRCA2 variants of the HRR proficient triple negative breast cancer cell line MDA-MB-231. We compared therapeutic response features such as RAD51 focus formation, cell cycle fraction alterations, DNA damage accumulation, colony formation, and cell death of these and other cell lines with and without intrinsic BRCA1/2 mutations. Results were confirmed in BRCA1/2 intact and deficient xenografts and PDX. Results Our targeted variants and cells with intrinsic BRCA1/2 mutations responded to low dose combination therapeutic treatment by G2M stalling, compounded DNA damage, severely attenuated colony formation, and importantly, increased cell death. In contrast, the parental MDA-MB-231 cells and other HRR proficient cell lines produced smaller cell populations with short term treatment, but with much less cumulative DNA damage, and minimal cell death. In animal studies, our BRCA-engineered hypomorphs and several independent PDX models with clinically relevant BRCA mutations were acutely more vulnerable to this drug combination. Conclusions We conclude that low dose DNA methyltransferase inhibition can cooperate with low dose PARP inhibition to increase DNA damage predominantly in cells with HRR deficiencies, ultimately producing more cell death than in HRR proficient tumors. We predict that clinical benefit will more likely be apparent in patients with DNA repair defective tumors and are focusing clinical exploration of this drug combination in these patients, with the goals of enhancing tumor cell death at minimal toxicities.https://doi.org/10.1186/s13058-024-01954-yBRCA1BRCA2PARP inhibitorDNMT inhibitorTalazoparibDecitabine |
| spellingShingle | Romain Pacaud Scott Thomas Sibapriya Chaudhuri Ann Lazar Luika A. Timmerman Pamela N. Munster Low dose DNA methyltransferase inhibitors potentiate PARP inhibitors in homologous recombination repair deficient tumors Breast Cancer Research BRCA1 BRCA2 PARP inhibitor DNMT inhibitor Talazoparib Decitabine |
| title | Low dose DNA methyltransferase inhibitors potentiate PARP inhibitors in homologous recombination repair deficient tumors |
| title_full | Low dose DNA methyltransferase inhibitors potentiate PARP inhibitors in homologous recombination repair deficient tumors |
| title_fullStr | Low dose DNA methyltransferase inhibitors potentiate PARP inhibitors in homologous recombination repair deficient tumors |
| title_full_unstemmed | Low dose DNA methyltransferase inhibitors potentiate PARP inhibitors in homologous recombination repair deficient tumors |
| title_short | Low dose DNA methyltransferase inhibitors potentiate PARP inhibitors in homologous recombination repair deficient tumors |
| title_sort | low dose dna methyltransferase inhibitors potentiate parp inhibitors in homologous recombination repair deficient tumors |
| topic | BRCA1 BRCA2 PARP inhibitor DNMT inhibitor Talazoparib Decitabine |
| url | https://doi.org/10.1186/s13058-024-01954-y |
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