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 (mt...

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Bibliographic Details
Published in:Cancer letters 2024-03, Vol.584, p.216608, Article 216608
Main Authors: Madorsky Rowdo, Florencia P., Xiao, Gu, Khramtsova, Galina F., Nguyen, John, Martini, Rachel, Stonaker, Brian, Boateng, Richard, Oppong, Joseph K., Adjei, Ernest K., Awuah, Baffour, Kyei, Ishmael, Aitpillah, Frances S., Adinku, Michael O., Ankomah, Kwasi, Osei-Bonsu, Ernest B., Gyan, Kofi K., Altorki, Nasser K., Cheng, Esther, Ginter, Paula S., Hoda, Syed, Newman, Lisa, Elemento, Olivier, Olopade, Olufunmilayo I., Davis, Melissa B., Martin, M. Laura, Bargonetti, Jill
Format: Article
Language:English
Subjects:
Antineoplastic Agents - pharmacology
Antineoplastic Agents - therapeutic use
BRCA1 Protein - genetics
BRCA1 Protein - metabolism
BRCA2 Protein - genetics
Breast Neoplasms - drug therapy
Breast Neoplasms - genetics
Breast Neoplasms - pathology
Cell Line, Tumor
DNA
DNA double-strand breaks
Female
Genes, p53
Humans
Lung Neoplasms - genetics
Mutant p53
Mutation
PARP inhibitor
Patient-derived tumor organoids
Poly(ADP-ribose) Polymerase Inhibitors - therapeutic use
Poly(ADP-ribose) Polymerases - metabolism
Synergistic cytotoxicity
Temozolomide - pharmacology
Temozolomide - therapeutic use
Tumor Suppressor Protein p53 - genetics
Tumor Suppressor Protein p53 - metabolism
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Summary: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. •We demonstrated that breast and lung patient derived tumor organoids (PDTOs) carrying mutant p53 (mtp53) present synergistic cytotoxicity to PARP inhibitor (PARPi) talazoparib and DNA damaging agent temozolomide.•Combination drug synergism was achieved when treating mtp53 containing, but not wild-type p53 expressing, PDTO.•Synergy resulted most likely from double-strand breaks in mtp53 expressing PDTOs that were not able to be repaired and subsequently led to cell death.•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.•We found that the combination drug synergism occurred in both breast and lung PDTO carrying wild type BRCA1/2 which demonstrated high strength for mtp53 as a significant biomarker.•This work suggests that in addition to BRCA1 mutation, TP53 mutation may be an additional predictor for cancer cell death following combination PARPi treatment.
ISSN:0304-3835
1872-7980
1872-7980
DOI:10.1016/j.canlet.2024.216608