Patient-derived tumor organoids with p53 mutations, and not wild-type p53, are sensitive to synergistic combination PARP inhibitor treatment

• Published in: Cancer letters Vol. 584; p. 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: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 01.03.2024
• 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; Mutant p53; DNA double-strand breaks; Patient-derived tumor organoids; Synergistic cytotoxicity; PARP inhibitor
• ISSN: 0304-3835; 1872-7980; 1872-7980
• DOI: 10.1016/j.canlet.2024.216608

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.