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

TitlePatient-derived tumor organoids with p53 mutations, and not wild-type p53, are sensitive to synergistic combination PARP inhibitor treatment.
Publication TypeJournal Article
Year of Publication2024
AuthorsRowdo FPMadorsky, Xiao G, Khramtsova GF, Nguyen J, Martini R, Stonaker B, Boateng R, Oppong JK, Adjei EK, Awuah B, Kyei I, Aitpillah FS, Adinku MO, Ankomah K, Osei-Bonsu EB, Gyan KK, Altorki NK, Cheng E, Ginter PS, Hoda S, Newman L, Elemento O, Olopade OI, Davis MB, M Martin L, Bargonetti J
JournalCancer Lett
Date Published2024 Mar 01
KeywordsAntineoplastic Agents, BRCA1 Protein, BRCA2 Protein, Breast Neoplasms, Cell Line, Tumor, DNA, Female, Genes, p53, Humans, Lung Neoplasms, Mutation, Poly(ADP-ribose) Polymerase Inhibitors, Poly(ADP-ribose) Polymerases, Temozolomide, Tumor Suppressor Protein p53

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.

Alternate JournalCancer Lett
PubMed ID38199587
PubMed Central IDPMC10922546
Grant ListR01 CA239603 / CA / NCI NIH HHS / United States
T32 CA203702 / CA / NCI NIH HHS / United States
UL1 TR002384 / TR / NCATS NIH HHS / United States
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Esther Cheng, D.O. Syed Hoda, M.D.

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