Patient-derived tumor organoids with p53 mutations, and not wild-type p53, are sensitive to synergistic combination PARP inhibitor treatment
Poly (ADP-ribose) polymerase inhibitors (PARPi) are used for patients with BRCA1/2 mutations, but patients with other mutations may benefit from PARPi treatment. Another mutation that is present in more cancers than BRCA1/2 is mutation to the TP53 gene. In 2D breast cancer cell lines, mutant p53 (mtp53) proteins tightly associate with replicating DNA and Poly (ADP-ribose) polymerase (PARP) protein. Combination drug treatment with the alkylating agent temozolomide and the PARPi talazoparib kills mtp53 expressing 2D grown breast cancer cell lines. We evaluated the sensitivity to the combination of temozolomide plus PARPi talazoparib treatment to breast and lung cancer patient-derived tumor organoids (PDTOs). The combination of the two drugs was synergistic for a cytotoxic response in PDTOs with mtp53 but not for PDTOs with wtp53. The combination of talazoparib and temozolomide induced more DNA double-strand breaks in mtp53 expressing organoids than in wild-type p53 expressing organoids as shown by increased γ-H2AX protein expression. Moreover, breast cancer tissue microarrays (TMAs) showed a positive correlation between stable p53 and high PARP1 expression in sub-groups of breast cancers, which may indicate sub-classes of breast cancers sensitive to PARPi therapy. These results suggest that mtp53 could be a biomarker to predict response to the combination of PARPi talazoparib-temozolomide treatment.
| Errataetall: |
UpdateIn: Cancer Lett. 2024 Jan 9;584:216608. - PMID 38199587 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - year:2023 |
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| Enthalten in: |
bioRxiv : the preprint server for biology - (2023) vom: 22. Juni |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Madorsky Rowdo, Florencia P [VerfasserIn] |
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| Links: |
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| Themen: |
DNA double-strand breaks |
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| Anmerkungen: |
Date Revised 24.02.2024 published: Electronic UpdateIn: Cancer Lett. 2024 Jan 9;584:216608. - PMID 38199587 Citation Status PubMed-not-MEDLINE |
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| doi: |
10.1101/2023.06.22.544406 |
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| funding: |
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| PPN (Katalog-ID): |
NLM365676829 |
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| 100 | 1 | |a Madorsky Rowdo, Florencia P |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Patient-derived tumor organoids with p53 mutations, and not wild-type p53, are sensitive to synergistic combination PARP inhibitor treatment |
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| 500 | |a Date Revised 24.02.2024 | ||
| 500 | |a published: Electronic | ||
| 500 | |a UpdateIn: Cancer Lett. 2024 Jan 9;584:216608. - PMID 38199587 | ||
| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 520 | |a Poly (ADP-ribose) polymerase inhibitors (PARPi) are used for patients with BRCA1/2 mutations, but patients with other mutations may benefit from PARPi treatment. Another mutation that is present in more cancers than BRCA1/2 is mutation to the TP53 gene. In 2D breast cancer cell lines, mutant p53 (mtp53) proteins tightly associate with replicating DNA and Poly (ADP-ribose) polymerase (PARP) protein. Combination drug treatment with the alkylating agent temozolomide and the PARPi talazoparib kills mtp53 expressing 2D grown breast cancer cell lines. We evaluated the sensitivity to the combination of temozolomide plus PARPi talazoparib treatment to breast and lung cancer patient-derived tumor organoids (PDTOs). The combination of the two drugs was synergistic for a cytotoxic response in PDTOs with mtp53 but not for PDTOs with wtp53. The combination of talazoparib and temozolomide induced more DNA double-strand breaks in mtp53 expressing organoids than in wild-type p53 expressing organoids as shown by increased γ-H2AX protein expression. Moreover, breast cancer tissue microarrays (TMAs) showed a positive correlation between stable p53 and high PARP1 expression in sub-groups of breast cancers, which may indicate sub-classes of breast cancers sensitive to PARPi therapy. These results suggest that mtp53 could be a biomarker to predict response to the combination of PARPi talazoparib-temozolomide treatment | ||
| 650 | 4 | |a Preprint | |
| 650 | 4 | |a DNA double-strand breaks | |
| 650 | 4 | |a PARP inhibitor | |
| 650 | 4 | |a Patient-derived tumor organoids | |
| 650 | 4 | |a mutant p53 | |
| 650 | 4 | |a synergistic cytotoxicity | |
| 700 | 1 | |a Xiao, Gu |e verfasserin |4 aut | |
| 700 | 1 | |a Khramtsova, Galina F |e verfasserin |4 aut | |
| 700 | 1 | |a Nguyen, John |e verfasserin |4 aut | |
| 700 | 1 | |a Olopade, Olufunmilayo I |e verfasserin |4 aut | |
| 700 | 1 | |a Martini, Rachel |e verfasserin |4 aut | |
| 700 | 1 | |a Stonaker, Brian |e verfasserin |4 aut | |
| 700 | 1 | |a Boateng, Richard |e verfasserin |4 aut | |
| 700 | 1 | |a Oppong, Joseph K |e verfasserin |4 aut | |
| 700 | 1 | |a Adjei, Ernest K |e verfasserin |4 aut | |
| 700 | 1 | |a Awuah, Baffour |e verfasserin |4 aut | |
| 700 | 1 | |a Kyei, Ishmael |e verfasserin |4 aut | |
| 700 | 1 | |a Aitpillah, Frances S |e verfasserin |4 aut | |
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| 700 | 1 | |a Osei-Bonsu, Ernest B |e verfasserin |4 aut | |
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| 700 | 1 | |a Altorki, Nasser K |e verfasserin |4 aut | |
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| 700 | 1 | |a Newman, Lisa |e verfasserin |4 aut | |
| 700 | 1 | |a Elemento, Olivier |e verfasserin |4 aut | |
| 700 | 1 | |a Davis, Melissa B |e verfasserin |4 aut | |
| 700 | 1 | |a Martin, M Laura |e verfasserin |4 aut | |
| 700 | 1 | |a Bargonetti, Jill |e verfasserin |4 aut | |
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