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Patient-derived tumor organoids with p53 mutations, and not wild-type p53, are sensitive to synergistic combination PARP inhibitor treatment.
- Source :
-
Cancer letters [Cancer Lett] 2024 Mar 01; Vol. 584, pp. 216608. Date of Electronic Publication: 2024 Jan 09. - Publication Year :
- 2024
-
Abstract
- 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.<br />Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
- Subjects :
- Female
Humans
BRCA1 Protein genetics
BRCA1 Protein metabolism
BRCA2 Protein genetics
Cell Line, Tumor
DNA
Genes, p53
Mutation
Poly(ADP-ribose) Polymerase Inhibitors therapeutic use
Poly(ADP-ribose) Polymerases metabolism
Temozolomide pharmacology
Temozolomide therapeutic use
Tumor Suppressor Protein p53 genetics
Tumor Suppressor Protein p53 metabolism
Antineoplastic Agents pharmacology
Antineoplastic Agents therapeutic use
Breast Neoplasms drug therapy
Breast Neoplasms genetics
Breast Neoplasms pathology
Lung Neoplasms genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1872-7980
- Volume :
- 584
- Database :
- MEDLINE
- Journal :
- Cancer letters
- Publication Type :
- Academic Journal
- Accession number :
- 38199587
- Full Text :
- https://doi.org/10.1016/j.canlet.2024.216608