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

Authors :
Madorsky Rowdo FP
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
Martin ML
Bargonetti J
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.)

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